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The Great Diseases
A collaborative approach to real
world science in the classroom
Infectious Disease
Neurological Disorders
Metabolic Disease
Cancer
Workbook
CANCER
Revati Masilamani, Ravi Subramanian and Karina Meiri
Table of Contents
Cancer
Student Workbook
Unit 1: What is cancer and why should we care? 4
Lesson 1.1 5
Lesson 1.2 12
Lesson 1.3 19
Lesson 1.4 27
Lesson 1.5 35
Unit 5: How do we treat cancer?
143
Lesson 5.1
144
Lesson 5.2153
Lesson 5.3160
Lesson 5.4168
Lesson 5.5175
Lesson 5.6182
Unit 2: What does it mean to be a 'normal' cell? 42
Lesson 2.1 43
Lesson 2.2 50
Lesson 2.3 57
Lesson 2.4 65
Lesson 2.5 72
Unit 3: How do normal cells become cancerous?
79
Lesson 3.1 80
Lesson 3.2 88
Lesson 3.3 95
Lesson 3.4101
Lesson 3.5107
Unit 4: How does cancer make us sick?
114
Lesson 4.1
115
Lesson 4.2122
Lesson 4.3129
Lesson 4.4136
2
Welcome to the
Cancer Module!
Outline
This module focuses on understanding cancer as a disease and the
challenges of diagnosing and treating it. The Cancer Module has five
units, each of which builds upon the others that came before it. The goal
of each unit is to answer a new question about cancer, and what this
means for our health.
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Throughout this module, you’ll have not only class lessons, but
also this workbook to guide you through your exploration of
Cancer. This workbook is designed to provide you with readings
to complement your class lessons. We have helped make your
reading of this workbook interactive by encouraging you to take
notes and answer questions throughout.
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a normal cell?
Unit 3: How do normal cells become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How do we treat cancer?
In Unit 1, we’ll begin our discussion by investigating how our understanding of what cancer is has changed over time, and what we currently
understand about the role of random mutation in causing cancer. From
there, in Unit 2, we’ll focus on how normal cells behave in their tissue
communities, and in particular their vulnerabilities to mutation. Then, in
Unit 3, we’ll zoom in on how cell function is disrupted in cancer. Next, in
Unit 4, we’ll take a broader approach and examine cancer as a disease
and the challenges of diagnosis. Finally, in Unit 5, we'll look at how we
diagnose and treat cancer and the challenges and opportunities for
designing better screens and treatments in the future.
3
Unit 1:
Unit 1: Introduction
Where are we heading?
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a 'normal' cell?
Unit 3: How does a normal cell become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How is cancer diagnosed and treated?
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Unit 1 focuses on what we currently understand
about cancer and how our perception of cancer has
changed over time.
Lesson 1.1 engages you with the idea that cancer is relevant to you,
and is not simply a disease of old age. Lesson 1.2 explores how
the historical context has always influenced how cancer has been
understood and will investigate the technological breakthroughs that
have led to our current understanding of cancer biology. Lesson 1.3
investigates how the three main theories of how cancer is caused
were reconciled when we finally understood that cancer is a disease
of DNA damage. Lesson 1.4 grapples with the challenges of establishing causation rather than correlation when dealing with diseases
of unknown and complex origins such as cancer. Lesson 1.5 will
explore how to assess the risk of developing cancer in order to make
informed choices about how to minimize that risk.
4
LESSON 1.1 WORKBOOK
Why should we care about cancer?
DEFINITIONS OF TERMS
Mortality rate – The rate at
which people die from a specific
cancer.
For a complete list of defined
terms, see the Glossary.
The first lesson focuses on two key issues you will
encounter as you move through the module: First,
cancer is not solely a disease of old age: Although
cancers usually reveal clinical symptoms in older
patients, they may have originated when that
patient was quite young. Second, a tumor that has
originated in a young person and spread from its
primary location soon after it develops will cause
significant mortality if it escapes detection and
evolves to resist treatment. For effective prevention we need to identify which tumors will evolve to
spread before they actually do so, as we shall see
in this lesson about Steve Jobs.
Why should I care about cancer?
About 8.2 million people die of cancer each year, making cancer the leading cause of death worldwide,
and the second leading cause of death in the United States (behind heart disease).
Many people believe that cancer is a disease of elderly people, and it is - if we confine our discussion to
clinical symptoms, which most typically appear at around 60 years of age. Even so, about 72,000 cases
of cancer are diagnosed in adolescents and young adults each year. Unfortunately while mortality rates
(frequency that people die from a particular cancer) have declined in older patients, they remain largely
unchanged in the 15-39 age group.
Wo r k b o o k
Lesson 1.1
This is largely due to misdiagnosis: young adults are simply not expected to develop cancer, so symptoms
may be left untreated for longer periods than in the elderly. As we will see, early identification of cancer is
the key to survival.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Carcinogen – An agent able to
cause cancer.
Wo r k b o o k
Lesson 1.1
A further issue that has only recently become apparent is that
there may be a significant delay between when a cancer develops
and when symptoms appear. During this time, as we will see, the
cancer is evolving so that it can resist the treatments we currently
have available. It follows then that it is critical to minimize the risks
of cancer developing in the first place, and this means becoming
aware of what these risks are. Some are undoubtedly genetic and
thus beyond our control, but others, such as exposure to cancercausing agents – carcinogens - are often avoidable. Thus, you may
have choices now that will profoundly impact your health in the
future. As we will, see minimizing cancer risks means being aware
of what those choices are.
MC Questions:
Figure 1: Steve Jobs
died of pancreatic cancer
at the age of 56. Building
computers with heavy
metals increased his
exposure to
cancer-causing materials.
We don’t have to look far for examples: Celebrities, who are under
constant media scrutiny, provide numerous instances of choices
made that turn out to have unfortunate consequences. Sometimes
are inadvertent: Steve Jobs was diagnosed with pancreatic cancer
in 2003, and died 8 years later at only 56, a relatively young age. As we all know, Jobs spent his teens
and twenties developing computer hardware, in the process exposing himself to heavy metals such
as cadmium and lead, which are now, but were not at the time, appreciated to be carcinogens. Did this
exposure increase his chances of developing cancer?
Figure 2: Patrick Swayze also
died of pancreatic cancer. He
exposed himself to cigarette
smoke almost 100 times a day
– another well-known cancer
causing agent.
Another example seems more clear-cut. Patrick Swayze
also died of pancreatic cancer at a young age - 57. Swayze
regularly smoked more than 60-80 cigarettes a day, exposing himself to tar compounds that have been well-known
carcinogens for over 70 years. While cigarette smoking is
linked primarily to lung cancer, it also leads to increased
risk of cancer in the throat, colon, breast, and other organs,
such as the pancreas. As a nicotine addict, could Swayze
have chosen to stop smoking?
1. Which of the following is NOT a
reason high-schoolers should care
about cancer?
aa. Cancer is often misdiagnosed
for people age 15-39;
bb. Cancer is the leading cause of
death in the US;
cc. Cancer mortality rates have not
decreased for young adults; or
dd. Choices made in high school
can affect the risk of developing
cancer later.
2. Which of the following might
increase your risk of developing
cancer?
aa. Heavy metals.
bb. Smoking.
cc. Excessive tanning.
dd. All of the above.
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6
LESSON READINGS
DEFINITIONS OF TERMS
Cancer – a disease caused by
an overgrowth of abnormal cells
with the capacity to spread to
other parts of the body.
Like many teenagers in the 60’s Diane Keaton, the Oscarwinning actress, describes herself as being “tan-obsessed”.
She was undoubtedly not helped by tanning creams and
lotions that were designed to increase sun exposure rather
than protect from it. It is only as the ozone layer has become
compromised that we have become aware how much UV
radiation from the sun contributes to skin cancer developing.
Diane Keaton paid the price for our lack of understanding when
she was making critical choices that would impact her later
health, but fortunately we all now have access to the information that sun exposure can be a cancer risk factor.
So even though cancer symptoms most frequently appear in
older people, cancer can, and often does, originate when we
are young. Fortunately we can make choices now that can influence the later outcome. The challenge is to identify all the risk
factors for cancer, so we can understand what all these choices
might be, and to develop effective treatments for when a choice
cannot be made.
Oncology – the study of cancer
as a disease.
3. What is true about cancer?
aa. It is a fatal disease.
cc. It is an infectious disease.
dd. It is a disease of abnormal cells.
dd. All of the above.
Figure 3: Diane
Keaton was diagnosed
with skin cancer at age
21. At that time sun
creams promoted exposure to UV radiation
rather than protecting
from it.
What is cancer?
Figure 4: Advanced tumors such as
the adrenal tumor above (left) are fed
by swollen tubes of blood that look like
legs on a crab (right: Blue King Crab). Our
modern term 'cancer' is Latin for crab.
Wo r k b o o k
Lesson 1.1
MC Questions:
It was the Greek physician Hippocrates (of
Hippocratic Oath fame) who came up with the
name 'cancer'. Some of his patients had large
red swellings under the skin with swollen blood
vessels protruding from the bulge. Hippocrates
thought that these swellings looked just like a crab
digging into sand, so he called them karkinos,
which was later modified to the Latin cancer. The
study of cancer as a disease is called 'oncology'
from the Greek word 'onkos', meaning 'swelling' or
burden.
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7
LESSON READINGS
Cancer is a disease caused by the rapid growth of
abnormal cells which may initially form a swelling or
tumor, but which eventually spread throughout the body.
By the end of this module we will understand more
clearly what causes drives the "abnormal" behavior.
DEFINITIONS OF TERMS
Tumor – a mass of rapidly
growing cells.
Benign tumor – a tumor that is
localized to a specific area of the
body and is not harmful.
Malignant tumor – a tumor that
is capable of spreading to
surrounding tissues and organs
and will cause disease.
Lymphatic system – the system
of vessels that moves immune
cells throughout the body. Like
the blood stream, but just for
white blood cells.
Wo r k b o o k
Lesson 1.1
What is the difference between cancer and a
tumor?
Figure 5: Warts (left) and moles
(right) are two examples of benign
tumors. They are localized and don’t
cause severe disease.
It is important from the outset to understand that there is
a critical distinction between a “tumor” and “cancer”.
A tumor is simply an overgrowth of cells that form a mass. Tumors are quite common and remain localized in one place without causing disease. This kind of tumor is called a benign tumor. A clear example of
a benign tumor is a wart or a mole.
On the other hand cancers are tumors that have evolved so they are now able to spread to other parts of
the body. These mobile tumors are called malignant tumors. It is important to note that even malignant
tumors are not necessarily life threatening. Some malignant cancers are not very mobile, and only spread
a little within the tissue, behaving essentially like benign tumors. These kinds of tumors are detectable and
if the whole tumor is removed, the patient will
be cured. It is tumors that migrate far away
from the primary site so that they escape
detection that are the most problematic.
Figure 6: Tumors can progress from benign
(not harmful) to metastatic (cancer causing),
but not all do. The challenge is identifying
which benign tumors will become malignant.
Once cancers enter the blood stream or
lymphatic system (the system that moves
immune cells throughout the body) they are
able to spread extensively throughout the
body. This movement is called metastasis,
from the Greek word for “next place”, and
cancers that have acquired this ability are
called metastatic tumors. Thus while all
cancers are tumors, but not all tumors are
cancers.
MC Questions:
4. Which is the first stage of developing
cancer?
aa. Benign tumor;
bb. Malignant tumor; or
cc. Metastatic tumor.
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5. True or false: Benign tumors always
become metastatic tumors
aa. True.
bb. False.
8
LESSON READINGS
Why is cancer so hard to treat?
In 1971, President Nixon a plan to cure cancer within the next 30 years. Fifty years later after billions of
dollars spent in research, we have made significant progress in the “War on Cancer” but by no means do
we have a cure. Has the American public got value for money? Why has cancer been such a challenge?
DEFINITIONS OF TERMS
Metastasis – the spread of malignant tumor cells from the site of
the primary tumor through blood/
lymph vessels.
Metastatic tumor – a cancer
that has acquired the ability to
enter the blood or lymph, and
spread through the body.
We can only begin to answer this question if we have a clear idea how much our ideas about what cancer
actually is have developed over the last fifty years. In fact the very notion that cancer as a disease evolves
over time – benign tumors acquire the ability to become mobile and metastasize, becoming malignant
in the process – is relatively recent. For more than thirty years our efforts focused almost exclusively on
the primary tumors, failing to appreciate how insidious metastases can develop very early and become
resistant to treatment. Thanks to the evolution in our understanding we can now appreciate that in order to
treat a cancer successfully we need to have answers two fundamental questions:
■■ When did the tumor first from?
■■ When did the tumor spread?
It is not enough to be able to locate the primary tumor. Often times we first notice a tumor indirectly
because it has disrupted bodily functions and caused symptoms such as breathlessness, pain and
nausea. But at this point the tumor has often already metastasized and become resistant to treatment.
It is critical to be able to identify a cancer before it metastasizes, which is often before it becomes
symptomatic.
The notion that it is critical to understand the progression from benign tumor to metastasis raises another
critical question: “How do we know which benign tumor will become metastatic?” We don’t need to treat
benign tumors that will never be problematic. Conversely we also don’t want to ignore a tumor that might
become metastatic. As we shall see in the next lesson (and in rest of the module), while our understanding of cancer as a disease has evolved significantly, until we can identify what causes a tumor to spread,
the ultimate challenge – of curing cancer will remain.
Wo r k b o o k
Lesson 1.1
MC Questions:
6. Why is cancer so hard to treat?
aa. We haven’t spent enough money
on research;
bb. Scientists are lazy; or
cc. We don’t know what causes
cancer to spread.
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7. What is the most important question
remaining in our understanding of
cancer?
aa. What causes cancer?
bb. What causes tumors to spread?
cc. What causes tumors to form?
dd. All of the above are important.
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9
STUDENT RESPONSES
List 3-4 behaviors that you have heard that increase the risk of developing cancer, and what types of cancer they are linked to.
To what extent are these behaviors under our control?
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Remember to identify your
sources
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Wo r k b o o k
Lesson 1.1
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10
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.1
DEFINITION
Benign tumor
A tumor that is localized to a specific area of the body and is not harmful.
Cancer
A disease caused by an overgrowth of abnormal cells with the capacity to spread to other parts of the body.
Lymphatic system
The system of vessels that moves immune cells throughout the body. Like the blood stream, but for white
blood cells.
Malignant tumor
A tumor that is capable of spreading to surrounding tissues and organs and will cause disease.
Metastasis
The spread of malignant tumor cells from the site of the primary tumor through blood/lymph vessels.
Metastatic tumor
A cancer that has acquired the ability to enter the blood or lymph and spread through the body.
Mortality rate
The rate at which people will die from a specific cancer.
Oncology
The study of cancer as a disease.
Tumor
A mass of rapidly growing cells in the body.
11
LESSON 1.2 WORKBOOK
How has our understanding of
cancer changed over time?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
Cancer has been recognized as a disease since
ancient times, but how we have described it
and sought to treat it has been influenced by the
prevailing interpretation of how our physiology
operates. This lesson describes the technical
breakthroughs that shaped our understanding of
cancer as a disease and shows how, surprisingly,
old ideas have become new again.
Cancer in ancient times: an imbalance of humors?
While Hippocrates first named cancer, it has been described as far back as 2600 BC. The Egyptian
physician Imhotep kept detailed records of many of his patients, commenting on one case - a woman with
‘swellings on the breast’ that her tumors could be “compared to the unripe hemat fruit, which is hard and
cool to the touch’. Imhotep was not optimistic about possible treatments stating starkly: “There is none.”
Even at that time, it was well understood to be a serious diagnosis.
The Greeks understanding of human physiology was strongly influenced by their preoccupation with
engineering, particularly fluid dynamics. Hippocrates believed that the human body is composed of four
major fluids, he called ‘humors’ each with characteristics of the four elements the Greeks had described:
■■ Blood was thought to have characteristics of air.
■■ Lymph was thought to have characteristics of water.
Wo r k b o o k
Lesson 1.2
■■ ‘Yellow bile’ was thought to have characteristics of fire.
■■ ‘Black bile’ was thought to have characteristics of earth.
MC Questions:
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1. What treatment for tumors persisted
for the longest time?
aa. Surgery;
bb. Bloodletting;
cc. Herbal potions;
dd. None of the above.
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12
LESSON READINGS
MC Questions:
The Greeks believed that disease occurs when one humor is in
excess over another. The forces influencing humor balance were
unclear although highly likely to be supernatural. To the Greeks
then, treating disease meant rebalancing the humors – for example
by preventative blood-letting and using laxatives. The notion that a
disease, like cancer, may have a specific physiological cause, simply
did not fit into their world-view.
DEFINITIONS OF TERMS
Inflammation – the body’s
immediate immune response to
infections. Typically produces
redness, fever, and itchiness.
Pus – a yellowish-white fluid consisting of dead cells, live immune
cells, and debris.
Pustule – a swelling of tissue
filled with pus. Can be located
anywhere on body.
Tubercule – Like a pustule, but
more often in found in lungs.
Jaundice – yellowing of the
skin, often associated with liver
disease.
Wo r k b o o k
Lesson 1.2
As time passed, and with the advent of Christianity, the notion that
the Gods were responsible for disease became less persuasive.
Galen of Pergamon, a 2nd century A.D. philosopher, surgeon, and
physician felt that linking observable physiological symptoms to the
humors would provide more scope for treatment.
Figure 1: Galen
of Pergamon was
the first person to
describe a way to
treat cancer.
■■ He suggested that the redness and fever of inflammation were
linked accumulation of blood.
■■ He suggested that the pus in pustules and tubercules was linked to accumulation of lymph.
2. Which of the following humors
was believed to be imbalanced in
cancer?
aa. Black Bile;
bb. Blood;
cc. Lymph;
dd. Yellow Bile.
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■■ He suggested that the yellowing of skin in jaundice was linked to accumulation of yellow bile.
■■ He suggested that the tumors found in cancer was linked to accumulation of black bile.
One obvious flaw in Galen’s idea was that no fluid ‘humor’ with characteristics of black bile has been
detected in tumors (which are generally solid). While Galen considered cancer an incurable disease, as
did Imhotep and Hippocrates before him, he nevertheless felt that tumors must have a natural cause and
therefore should be preventable. His solution was to bleed the patient to the humors and prevent accumulation of the elusive black bile, which in turn should prevent tumors forming.
Galen’s theory of black bile dominated medicine for over a thousand years, effectively short circuiting
rational study into disease and how they could be treated. This was particularly true for cancer, since
the ‘black bile’ theory was already without basis. Lack of rational study didn’t prevent remedies being
proposed (and used) however. Among the most notable included: boar’s tooth, fox lungs, rasped ivory,
ground white-coral, hulled castor and tincture of lead.
3. Which of the following was a major
achievement by Galen?
aa. Accurate description of human
anatomy;
bb. Realizing that cancer had an
actual cause;
cc. Discovery of black bile;
dd. All of the above.
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LESSON READINGS
Galen made a second contribution to the study of disease: a deep appreciation for the importance of
understanding anatomy. In this he was thwarted by the cultural taboos around handling corpses that
had persisted as a legacy of Roman times and that prevented him from working on human cadavers. He
attempted to get around these proscriptions by vivisecting animals and his meticulous work persisted as
the go-to studies in anatomy until the Renaissance, which ushered in a new ethos of understanding the
world through empirical research and observation. Galen’s work began to be re-assessed.
DEFINITIONS OF TERMS
Moveable tumor – type of tumor
described by John Hunter, now
known as a “solid” tumor. These
tumors could be felt and moved
when touched.
Wo r k b o o k
Lesson 1.2
Cancer moving forward: from humors to tumors
Figure 2: Andreas
Vesalius wrote a
seminal work on
human anatomy and
was first to disprove
the black bile theory
of cancer.
Andreas Vesalius seized the possibilities that arose when the
taboos about human dissection finally crumbled. His seminal work,
the seven-volume De humani corporis fabrica (On the fabric of
the human body) published in the 16th century challenged Galen
‘drawing for drawing’ - clearly demonstrating the major differences
between humans and the dogs Galen had drawn. This was the
first book to provide a detailed road map of the human body, and
Vesalius’s sketches of the circulatory system were quickly used
to identify the sites that should be bled to squeeze humors out of
afflicted areas. Vesalius succeeded in transforming preventative
blood letting from an inefficient, ineffective treatment, to an efficient,
ineffective treatment!
By mapping the circulatory and lymphatic systems Vesalius was
able to pin down the physiological basis for blood and lymph. ‘Yellow
bile’ he located in the liver. But despite his best efforts ‘black bile’
remained elusive. “If there is no black bile in the body” he wondered
“How are tumors formed?”
This was clearly an unsolvable conundrum and interest moved away from how tumors form to what could
be done about them. By the 1760s, dissections had become commonplace, and surgery was starting
to be more successful. The Scottish surgeon John Hunter pioneered the surgical removal of ‘moveable’
tumors. These tumors, located just below the skin, were solid and moved when touched. The notion that
solid tumors could be removed finally squelched the idea that they formed from accumulation of black bile.
But if they weren’t made of humors, what were they made from?
MC Questions:
4. Why did Galen dominate the field of
medicine for over a thousand years?
aa. He offered the best explanation
possible at the time;
bb. Cultural taboos of handling
corpses prevented learning
about human anatomy;
cc. Galen’s work was readily
available;
dd. All of the above.
5. Which of the following humors was
Vesalius able to identify through his
research? (Circle all correct.)
aa. Black bile.
bb. Blood.
cc. Lymph.
dd. Yellow Bile.
6. True or False: Breast tumors are a
type of ‘moveable’ tumor.
aa. True.
bb. False.
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14
LESSON READINGS
DEFINITIONS OF TERMS
Primary tumor – the original
organ in which a cancer is identified.
Secondary cancer – other
organs in which a cancer forms
after it has undergone metastasis.
Recurrence – the return of
cancer in either the primary organ
or secondary organs.
Antonie van Leeuwenhoek (who was the first to look down a
microscope at a flea, as we saw in the Infectious Disease module)
made the landmark discovery that our bodies are composed of
billions of cells. While his idea also gained general acceptance
during the 17th century, the logical connection between van
Leeuwenhoek’s and Turner’s work – that solid tumors were also
formed from cells – was not made until the 19th century, by
Rudolph Virchow. In 1858, Virchow proposed that, “Omnis cellula
e cellula” (Every cell originates from another cell) implying that
tumors too were actually a large mass of cells that had originated
from other cells but were now behaving abnormally.
Cancer now: from tumors back to
humors?
Figure 3: Antoine van
Leeuwenhoek proposed
that our bodies were
composed of 'cells', and
not 'fluids', so cancers
were cell-based.
The notion that tumors arise from the same cells that form the rest of the human body was a paradigmshifting discovery. Far from being a supernatural phenomenon, Cancer had a solid physiological cause:
These cells had become abnormal. Surely it was now a problem with a simple answer? If abnormal cells
were the cause of cancer as a disease, then removing or killing the abnormal cancer cells should cure the
disease.
Radical surgery – the complete
removal of an organ including
surrounding tissue that supports
the organ in the effort to completely remove all cancer cells.
Figure 4: Rudolph
Virchow believed that
cancer cells came from
normal cells.
Wo r k b o o k
Lesson 1.2
MC Questions:
By the 1800s, surgery had improved to the point that it could effectively
remove many tumors. However, a sizeable percentage of people who
had had their tumors removed would see their cancer recur. Surgeons
assumed that the surgery had simply left some cancer cells behind. In
1882, William Halsted, a surgeon at Johns Hopkins Hospital introduced
radical surgery for removing breast tumors. In this case the term
“radical” comes from the Latin radix, radicalis, meaning “root”. Halstead
wanted to root out every abnormal cell that could cause the tumors to
recur.
7. Which of the following did not
cause a paradigm change in our
understanding of cancer? (Circle all
that apply)
aa. Galen’s black bile theory.
bb. John Hunter’s moveable tumor
theory.
cc. Van Leeuwenhoek’s discovery
of cells.
dd. Virchow’s cellular model of
cancer.
8. If a tumor originated in the lung and
then metastasized to the bone, what
would the primary cancer be?
aa. Lung cancer.
bb. Bone cancer.
cc. Both a & b.
dd. None of the above.
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15
LESSON READINGS
DEFINITIONS OF TERMS
Metastasis – the spread of malignant tumor cells to other parts
of the body through blood/lymph
vessels. (noun)
Metastasize – the spreading of
malignant tumor cells to other
parts of the body. (verb)
'Seed and fertile soil' theory –
a theory by Stephen Paget that
proposed that tumors only form
when they are in the appropriate
environment for their growth.
Wo r k b o o k
Lesson 1.2
Halsted felt that removing as much tissue as possible
would solve the problem. He performed surgeries
removing the entire breast, as well as chest muscles,
and lymph nodes in the arm-pit. These radical surgeries were extremely disfiguring to the extent that many
women were left unable to stand upright because the
muscles that controlled posture had been removed.
These heroic efforts did indeed control recurrence
at the primary site, however they failed to solve a
second, even more insidious problem. In many cases
when tumors recurred they appeared in secondary
sites a distance from the primary tumor. Following
breast removal secondary cancers in the lungs and
bone were not unusual. Doctors and surgeons were
flummoxed.
Figure 5: Radical surgery of the
breast removes the entire breast,
muscle, and lymph nodes in the arm
pit.
The British surgeon Campbell de Morgan, proposed the logical, but nonetheless provocative idea that
once a tumor had formed in a primary organ it might acquire the ability to migrate to other tissues. The
notion of cancer cells traveling in blood was not unknown – blood cancers were being studied. But de
Morgan noticed that after solid tumors had been detected in a primary organ they were often also found in
the lymph nodes surrounding the organ. This migration of the tumors was described as 'metastasis', from
the Greek for “next place”.
Primary tumors seemed to have distinct preferences for where they migrate to. The surgeon Stephen
Paget proposed the theory that the abnormal cells in tumors can act like ‘seeds’ and seek ‘fertile soil’. Not
all organs are fertile soil for each tumor. Paget’s ‘seed and fertile soil’ theory was revived as a basis for
study in the 1980s, when the importance of metastasis in cancer mortality was finally appreciated.
Our evolving understanding of physiology has driven how we have thought about. We once thought our
body is a system of fluids, and we now realize it is a community of cells. We once thought cancer was
a judgment of the Gods, now we know it comes down to cells behaving in anti-socially. But we can also
argue that our understanding of cancer has come full circle – from humor to tumor and now back to
humor — even if it's the circulatory and lymph systems rather than black bile.
MC Questions:
9. Which of the following paradigm
changing descriptions of disease
are relevant to cancer ? (Circle all
correct.)
aa. Galen’s black bile theory.
bb. John Hunter’s moveable tumor
theory.
cc. Virchow’s cellular model.
dd. Stephen Paget’s seed and fertile
soil theory.
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10.True or false: The seed and fertile
soil hypothesis attempts to explain
why secondary cancers don’t appear
in every organ.
aa. True.
bb. False.
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STUDENT RESPONSES
Give two examples of how the black bile hypothesis is similar to our current understanding of cancer as a disease, and two
examples of how the black bile hypothesis is different.
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Wo r k b o o k
Lesson 1.2
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17
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.2
DEFINITION
Inflammation
The body’s immediate immune response to infections. Typically produces redness, fever, and itchiness.
Jaundice
Yellowing of the skin, often associated with liver disease.
Metastasis
The spread of malignant tumor cells to other parts of the body through blood/lymph vessels. (noun)
Metastasize
The spreading of malignant tumor cells to other parts of the body. (verb)
Moveable tumor
Type of tumor described by John Hunter, now known as a ‘solid’ tumor. These tumors could be felt and
moved when touched.
Primary cancer
The original organ in which a cancer is identified.
Pus
A yellowish-white fluid consisting of dead cells, live immune cells, and debris.
Pustule
A swelling of tissue filled with pus. Can be located anywhere on body.
Radical surgery
The complete removal of an organ including surrounding tissue that supports the organ in the effort to
completely remove all cancer cells.
Recurrence
The return of cancer in either the primary organ or secondary organs.
Secondary cancer
Other organs in which a cancer forms after it has undergone metastasis.
'Seed and fertile soil'
theory
A theory by Stephen Paget proposing that tumors only form when they are in the appropriate environment
for their growth.
Tubercule
A swelling of tissue filled with immune cells. Like a pustule, but more often in found in lungs.
18
LESSON 1.3 WORKBOOK
What do we know about how
cancer is caused?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
As our understanding of cancer as a disease has evolved we have increasingly
turned our attention to questions of what causes cancer in the first place. This
lesson shows how three competing theories about the cause of cancer - infectious
agents, environmental toxins, and genetics were reconciled. How? The answer, as
you will see, lies in our DNA.
What causes cancer? — carcinogens
In that last lesson, we discussed how our understanding
of cancer as a disease shifted as our understanding of
physiology evolved. Until we progressed beyond belief
in the influence of supernatural forces, such as gods or
spirits, the question ‘What causes cancer?’ would not get
a rational answer. It was the rise of empiricism - the view
that natural phenomena occur because of natural forces
– in the 16th century that set the stage for rational studies
into the natural causes of cancer.
Empiricism – the view that
things occur because of natural,
observable causes.
Wo r k b o o k
Lesson 1.3
One of the first approaches was simply to determine what
different people suffering from a similar cancer had in
common. Percival Pott, an English physician working in
the 16th century employed this approach very successfully
to discover the cause of scrotal cancer. Pott noticed that
young chimney sweeps were particularly susceptible to
scrotal cancer. Chimney sweeps were usually poor, indentured orphans, small enough to fit up chimney flues. They
were often sent up chimneys naked and lubricated in oil.
Figure 1: Percival Pott (left)
was the pioneer of the field of
epidemiology, the study of patterns
of disease within a population.
He identified the cause of scrotal cancer among young chimney
sweeps (right) in London.
MC Questions:
1. What would be the first step in
identifying the cause of a specific
cancer?
aa. Determine how people with that
cancer are similar.
bb. Inject people with the agent you
think might cause the cancer.
cc. Do studies to see if the agent
can cause the cancer in rats.
dd. All of the above would be a good
first step to identify a cause of
cancer.
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LESSON READINGS
Careful observation (coupled with poor hygiene) allowed him to detect the “lodgement of soot in the rugae
[ridges] of the scrotum”. Pott’s work identified exposure to chimney soot as the culprit in scrotum cancer,
leadubg the British government to improve working conditions for children that reduced their exposure to
chimney soot. Potts was one of the first pioneers of epidemiology, the study of how patterns of disease
are found in a population.
DEFINITIONS OF TERMS
Epidemiology – The study of
how patterns of disease are
found in a population.
More than a century after Pott’s work, two Japanese scientists, Katsusaburo Yamagiwa and Koichi
Ichakawa, confirmed Pott’s finding by painting the tar found in chimney soot onto rabbits’ skins. They
hypothesized that the tumors that developed where the tar was applied were caused by chemicals in the
tar. They then identified which chemicals in the tar were responsible, and coined a new term for these
chemicals - carcinogens.
But it soon became clear that cancer could be caused by other agents, not just carcinogens, and the race
was on to identify what these agents are, and how they work.
What causes cancer? - pathogens
Carcinogen – a substance
capable of causing cancer in
living tissue.
Before Louis Pasteur, the popular notion was that illness is caused by “bad air”. After Pasteur proposed
the germ theory of infectious diseases, the idea that disease is caused by pathogens became very
attractive. Could pathogens also cause cancer? To many scientists the idea that pathogens could be
carcinogenic was very plausible, and they set about identifying them.
Sarcoma – a cancer that forms
in nerves, muscles, joints, bones
or blood vessels (<1% of human
cancers).
Wo r k b o o k
Lesson 1.3
Figure 2: Rous showed that he
was able to transfer cancer (red
arrow) in chickens, suggesting
cancer was an infectious disease.
By 1911, viruses were being isolated, and Peyton Rous
had the idea that viruses might also be able to cause
tumors. He started off with chicken sarcomas (a type of
solid tumor), isolated the tumors, ground them up and
passed the mixture through a very small filter that would
permit a virus to pass through but would hold back other
types of pathogens. Then he injected the filtrate into
healthy chickens. Sure enough the healthy chickens
developed sarcomas too. Rous went one step further.
He made filtrates from the newly formed sarcomas and
injected them into more healthy chickens. These filtrates
too caused sarcomas. Rous identified the infectious
agent that caused the tumors as a new virus and called
it Rous sarcoma virus after himself and the type of
tumors it caused.
MC Questions:
2. True or False: A carcinogen is any
chemical agent that causes cancer
aa. True.
bb. False.
3. Why were pathogens so popular
as a model to explain the cause of
cancer? (Circle all correct.)
aa. Louis Pasteur had developed the
germ theory, so people thought
diseases should have a specific
cause.
bb. The experimental evidence
linking carcinogens to cancer
was indirect.
cc. The pathogen model was
favored by strong personalities.
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LESSON READINGS
After Rous’ discovery, many more viruses capable of causing tumors in animals like mice, rats and cats
were identified including viruses that caused leukemia and lymphoma (cancers of the immune system)
as well as breast cancer. Puzzlingly though, none of these cancer-causing viruses were found in humans.
Nor were there any other viruses associated with human cancers. If viruses cause cancer, why couldn’t
anyone find viruses in human cancers?
What causes cancer? - our genes
DEFINITIONS OF TERMS
Leukemia – a cancer of white
blood cells.
Lymphoma – a cancer of lymph
nodes, or other cells of the immune system.
Retinoblastoma – a specific
type of cancer affecting retina
cells of the eye that is commonly
inherited.
Wo r k b o o k
Lesson 1.3
At the same time cancer virologists were isolating the viruses that caused cancers in animals, yet other
scientists had turned their attention to genes. Even as far back as the 19th century physicians had noticed
that some types of cancers, particularly of the breast and ovaries, ran in families, but what this observation meant was not yet clear. Then, in 1872, a Brazilian ophthalmologist, Hilrio de Gouvea, successfully
treated a young boy with a rare eye cancer called retinoblastoma by removing the affected eye. His
patient grew up and married a woman with no family history
of cancer. The couple had several children, and two of their
daughters developed the same type of retinoblastoma that their
father had suffered from. Both died. de Gouvea believed this
provided evidence that retinoblastoma is inherited, not caused by
environmental carcinogens or pathogens.
Around the same time, Theodor Boveri, an assistant of Rudolph
Virchow (who we read about in the last workbook) was studying mitosis by treating sea urchin eggs with a dye that stained
chromosomes. He observed that if the eggs were fertilized
by multiple sperm their progeny would have aberrant chromosomes. In a burst of creativity, he likened this chromosomal
chaos to cancer. In his 1914 manuscript, “Concerning the Origin
of Malignant Tumors”, he argued that cancer too was caused by
disrupting chromosomal order and structure.
Figure 3: Fertilized sea
urchin eggs. Boveri saw
massive chromosome
disruption when the eggs
were hyper fertilized.
In retrospect, given how little we understood at the time about what chromosomes actually do, this logical
leap was extraordinary. However because so little was known about how cells worked internally, it did
not answer the question: “How could external agents like carcinogens and viruses as well as internal
structures like chromosomes all be responsible for causing cancer?” With little to reconcile these opposing views, the cancer field remained divided into 3 camps until well into the 20th century.
MC Questions:
4. Which of the following were a
proposed cause of cancer? (Circle
all correct.)
aa. Environmental factors.
bb. Viruses.
cc. Genetic inheritance.
dd. Animal bites.
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5. Which of the following cancers were
studied through observation, not
direct experimentation? (Circle all
correct.)
aa. Scrotal cancer in chimney
sweeps.
bb. Familial retinoblastoma.
cc. Lymphoma.
dd. Leukemia.
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LESSON READINGS
A unified theory of cancer emerges
Eventually a number of discoveries began to build bridges between these seemingly irreconcilable
theories: One of the first, in 1915, was by Thomas Hunt Morgan, who showed that chromosomes are
like necklaces, the beads on the necklace being traits or genes. Morgan suggested that the aberrant
chromosomes Boveri had seen in the hyper-fertilized sea urchin eggs were caused because the genes
on the chromosomes had been disrupted. Morgan’s work was followed by Oswald Avery’s discovery in
the 1940’s that genes are encoded by DNA, and Watson and Crick in the 1950’s of the code DNA uses to
store information about what each gene does.
DEFINITIONS OF TERMS
Mutagen – any chemical or
agent that is capable of mutating
DNA sequence.
Oncogene – a mutated gene
that, when expressed, promotes
cancer in cells.
Proto-oncogene – a gene that
when expressed acts as a growth
factor, and that, when mutated,
will become an oncogene and
promote cancer in cells.
Wo r k b o o k
Lesson 1.3
The logical interpretation was that
if DNA in normal cells becomes
damaged, the cells will form tumors.
But how could external agents like
carcinogens, or infectious agents,
like viruses all damage DNA? In the
1970’s, Bruce Ames used bacteria,
which divide, and therefore mutate,
very rapidly, to show that how carcinogens cause DNA to mutate. Importantly, how well a potential carcinogen
mutagenizes DNA in bacteria directly
relates to its ability to induce a tumor
in rats.
MC Questions:
6. Whose work explained how
carcinogens cause cancer by
mutating a gene’s DNA?
aa. Theodor Boveri.
bb. Bruce Ames.
cc. Varmus and Bishop.
dd. All contributed in explaining this
model.
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Figure 4: The Ames Test examines how
chemicals can mutate bacteria such that they are
able to grow on plates that they normally are
incapable of growing. The more mutagenic the
compound, the more bacteria will grow, and the
more likely it is carcinogenic.
The Ames test uses a specific
bacterium that already has a mutation in a gene involved in making the amino acid histidine, which the
bacteria needs for growth and survival. As a result these defective bacteria grow very poorly. There are
two ways we could overcome the defect in histidine: We could give the bacteria a source of histidine so
they wouldn’t have to make it themselves – by incorporating histidine into the agar in the petri dish for
example. Alternatively we could treat the bacteria with a chemical that would mutate the mutation, making
the bacteria normal again! This is the basis for the Ames test: The defective bacteria are treated with a
possible mutagen and then their ability to grow is monitored. If the mutagen fixes the existing mutation,
the bacteria will be able to make their own histidine again, and will grow normally on agar, even without a
histidine supplement.
7. True or False: The Ames test
can show that a chemical is a
carcinogen.
aa. True.
bb. False.
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LESSON READINGS
So now we can see how carcinogens turn normal cells into tumors by mutating their DNA, but how
do viruses cause tumors to form? Carrying the gene idea forward, a group of scientists identified that
the Rous sarcoma virus needs a certain gene in order to cause tumors. They called this gene src
(pronounced ‘sarc’, a diminutive of sarcoma). Because of its ability to cause cancer they called src an
oncogene. The virus camp was excited because they finally had a model – when viruses infect cells they
cause cancer via oncogenes.
DEFINITIONS OF TERMS
Synergistic – phenomena where
two factors increase the risk of
cancer in combination than each
factor by itself.
Then disaster seemed to strike! Another group, led
by Harold Varmus and Michael Bishop made the
surprising discovery that src is present in cells of
most species, including humans. But if src is already
present in normal cells how could it cause cancer?
It didn’t make any sense. Finally Varmus and Bishop
figured out that in normal cells the src gene is important to promote growth and survival, but in viruses it
has been mutated so it can cause cancer. Viruses
must have originally picked up src when they infected
normal cells and then mutated it as they replicated.
They called the host cell src genes, proto-oncogenes
to emphasize that they came before the viral oncogenes (protos is Greek for “first”). Soon many other
proto-oncogenes and oncogenes were identified.
Figure 5: The unified model for
cancer is that an agent mutates
proto-oncogene DNA to become an
oncogene, which makes a protein that
promotes cell growth and survival and
development of cancer.
A unified theory of cancer
With this last piece of the puzzle a unifying theory of cancer became could be built:
■■ Proto-oncogenes normally promote cell growth and survival and become mutated to cause cancer.
■■ The mutations can either occur randomly or be induced by carcinogens.
■■ Or they can be introduced into cells by viruses that contain the mutated oncogenes.
■■ If the mutations are found in germ cells (like eggs and sperm) they will be inherited.
Wo r k b o o k
Lesson 1.3
It is important to emphasize that in order for a carcinogen to cause cancer it must mutate a protooncogene in just the right way. But mutations are random, so not all mutations of a proto-oncogene will be
cancer-causing and in fact most mutations won’t even affect proto-oncogenes at all. So we simply can’t
MC Questions:
8. True or False: Carcinogens randomly
mutate DNA to cause cancer.
aa. True.
bb. False.
9. Why is it so difficult to establish that
a substance is a carcinogen? (Circle
all correct.)
aa. Exposure doesn’t always cause
cancer.
bb. Carcinogens randomly mutate
DNA and not all mutations will
lead to cancer.
cc. We don’t know all the protooncogenes involved in cancer.
dd. Few cancers are caused by
pathogens.
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LESSON READINGS
DEFINITIONS OF TERMS
Carcinogen – An agent able to
cause cancer.
Wo r k b o o k
Lesson 1.3
predict whether a specific exposure to a carcinogen will cause cancer. By the same token though, the
more exposure occurs, the more likely the critical mutation will happen.
MC Questions:
But this is not the full story either: As we saw with RSV, a mutation in a single proto-oncogene can cause
a tumor to form, but will it be sufficient to cause actual cancer? We will see in Chapter 3 that more than
one proto-oncogene needs to be mutated for a tumor to turn into cancer. In fact there is a whole other
class of genes (called tumor suppressors) that can also be mutated to lead to cancer - we will talk about
them too in Chapter 3. In fact the reason why cancer symptoms often appear later in life, is because it
takes a while for mutations in different proto-oncogenes to accumulate
10.Which of the following might
increase your risk of developing
cancer?
aa. Heavy metals.
bb. Smoking.
cc. Excessive tanning.
dd. All of the above.
It should be clear by now that cancer may have many different causes: For instance, lung cancer can
occur through random mutation of proto-oncogenes, or there may be a genetic predisposition, or it may
be caused by environmental carcinogens such as the coal tar compounds in cigarette smoke or asbestos.
The effects can be synergistic - a genetic predisposition for lung cancer because of a proto-oncogene
mutation coupled to prolonged exposure to carcinogens in smoke asbestos will increase the chances of
lung cancer developing.
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STUDENT RESPONSES
Describe the link between how (a) a carcinogen, (b) a pathogen, and (c) an inherited mutation, all promote cancer.
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Wo r k b o o k
Lesson 1.3
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25
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.3
DEFINITION
Carcinogen
An agent that is responsible for, or associated with cancer.
Empiricism
The view that things occur because of natural, observable causes.
Epidemiology
The study of how patterns of disease are found in a population.
Leukemia
A cancer of cells of the immune system.
Lymphoma
A cancer of lymph nodes, or other cells of the immune system.
Mutagen
Any chemical or agent that is capable of mutating DNA sequence.
Oncogene
A mutated gene that, when expressed, promotes cancer in cells.
Proto-oncogene
A gene that serves a normal function in a cell, and when mutated, will become an oncogene an promote
cancer in cells.
Retinoblastoma
A specific type of cancer affecting retina cells of the eye that is commonly inherited as a disease.
Sarcoma
A specific type of cancer that is caused by Rous Sarcoma Virus in chickens.
Synergistic
The phenomena where two factors increase the risk of cancer in combination than each factor by itself.
26
LESSON 1.4 WORKBOOK
How can we identify carcinogens?
In order to fully understand cancer and to develop
effective treatments we need to know how it is
caused. This lesson compares Koch’s postulates –
the criteria that must be satisfied in order to establish an agent as infectious, with Hill’s postulates,
the criteria that must be satisfied to establish an
agent as carcinogenic. But how can we definitively
prove that a carcinogen causes cancer in humans
if we clearly can’t ethically cause the disease? This
problem results in certain ambiguities about what is
a carcinogen and what is not that companies have
exploited to avoid liability.
So how can we determine whether something “causes"
cancer?
Wo r k b o o k
Lesson 1.4
In 1947 the British Ministry of Health became aware that lung cancer deaths had risen nearly 15-fold
compared to the previous two decades. It seemed that an unprecedented epidemic was in progress. In
response, the Medical Research Council, the body responsible for handling government-funded scientific
research in Britain, organized a conference of experts to investigate and hopefully find a cause for this
unexpected rise. The conference decided to establish a thorough study, run by the statistician Austin
Bradford Hill, to identify risk factors for lung cancer. Hill was given a shoestring budget, which forced him
to hire inexperienced staff such as Richard Doll, who, though he was a medical researcher, had never
organized a study of such scale or significance before.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Case-control study – a study
where patients with a disease and
patients without disease are reviewed to identify patterns that may
have led to development of disease.
Cases – the group within a
case-control study that developed
disease.
Controls ¬– the group within a
case-control study that did not
develop disease.
Over-reported – when survey respondents claim they partook of an
activity more than they actually did.
Under-reported – when survey respondents claim they partook of an
activity less than they actually did.
Interventional study – a study
where one group is given a treatment to evaluate the effect of that
treatment on people.
Wo r k b o o k
Lesson 1.4
Doll and Hill worked together to design a casecontrol study with the goal of figuring out what
the lung cancer patients had in common. They
interviewed patients admitted to one of 20 London
hospitals for either lung cancer (cases) or other
illnesses (controls), about various aspects of
their life, including how close their homes were to
gasworks, how often they ate fried fish, whether
they ate bacon, sausage or ham for dinner, and
their smoking habits. Doll and Hill hoped these
questions would identify factors that led one
group to developing lung cancer, while the other
group remained healthy.
MC Questions:
1. True or false: A case-control study
involves providing a treatment to a
'case' group and not to a 'control'
group.
aa. True.
bb. False.
Figure 1: Design of a case-control
experiment. By examining the histories of
two distinct populations, one can identify
risk factors that led one group to acquire
disease while the other group remained
healthy.
Doll and Hill’s study (and another by a group in
the US) showed the same result in two different
populations, in two different countries. Even
though the studies used different methodologies they both arrived at the same conclusion: smoking
predisposes people to lung cancer. Perhaps more astonishing, the magnitude of risk in both studies was
almost identical, proving the strength of the association of smoking to lung cancer.
Despite the seemingly convincing results, Hill was very concerned that his study might be biased. In
particular he was worried that the extent of smoking was over-reported in lung cancer victims and
under-reported in the control group. If this was the case, the relevance of smoking in lung cancer
would be skewed. He realized that the best way to conclusively prove a link would be to randomly assign
patients to two different groups one of which would smoke while the other would not. He would then follow
how frequently members of each group would develop cancer. As we saw in the Metabolic Diseases
module, this type of interventional study is the only way to conclusively prove causation, but that
ghoulish human experiment would violate many ethical principles in medicine.
So, Hill did the next best thing, which was to simply observe a population of people that contained
both smokers (treatment group) and nonsmokers (control group) for 20 months and then determine the
frequency of lung cancer deaths in each group. There were 40,000 people in the study, and 789 died over
the 20-month period, 36 due to lung cancer. Of those 36, every single one was a smoker! The relationship
between smoking and lung cancer was beyond statistical.
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2. Why can’t Koch’s postulates be
applied to finding causes of cancer?
(Circle all correct.)
aa. You can’t identify patterns of
exposure for carcinogens and
cancer.
bb. You cannot inject carcinogens
into humans to cause cancer.
cc. Few cancers are caused by
pathogens.
dd. You cannot isolate carcinogens
from cancer patients.
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LESSON READINGS
DEFINITIONS OF TERMS
Hill’s Postulates – a list of
epidemiological criteria that set
the minimal evidence necessary
to show causality.
When these studies were eventually
published in 1956, tobacco companies
quickly realized the implications and
began a tightly orchestrated disinformation
campaign. They published a newspaper
advertisement stating: ‘recent reports on
experiments with mice have given wide
publicity to a theory that cigarette smoking
is in some way linked with lung cancer in
human beings’ a clear mis-statement of
facts that, by tying Hill’s data to mice rather
than humans, made the link appear less
relevant. Tobacco companies also accused
scientists of conflating a correlation between
smoking and lung cancer into a causal
relationship.
3. True or False: All 9 of Hill’s
postulates must be met in order to
show a relationship is causal.
aa. True.
bb. False.
Figure 2: Design of an interventional study.
Groups are randomly assigned to an intervention/treatment or control group. Effects of that
intervention are measured after some time, and
control and intervention groups are compared.
Causation vs. Correlation: Hill’s postulates
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.4
MC Questions:
This battle was not only over a specific link between smoking and lung cancer, it was over the merits of
the emerging field of epidemiology that had started with Percival Pott and scrotal cancer. As we learned
in the Infectious Disease module, the only way that we can actually prove that a pathogen causes an
infectious disease is first to isolate it and then to show that the isolated pathogen causes disease in a
susceptible host. Rous used the exactly the same principle to show his RSV caused chicken sarcoma.
However Rous was fortunate in two ways we are often not: first, unlike most carcinogens his virus would
cause the tumor after only one exposure. Second, Rous was not working with human cancer. As Bradford
Hill also realized, it's simply not ethical to try to identify a potential human carcinogen by inducing to
produce cancer in humans. This left the cancer field in a quandary. Epidemiologists perform observations
that can at best only demonstrate strong correlations, and Koch’s postulates would not apply in a complex
disease such as cancer where multiple mutations might be needed for cancer to develop. Were we ever
going to prove causation?
Grappling with that question, and taking his cue from Koch and his postulates, Bradford Hill came up with
a list of 9 distinct criteria, that, if they were all met, would provide very strong evidence supporting causality
for any chronic and complex human disease. Though Hill realized that the only way to prove causality
is with Koch-type studies that were neither feasible in humans, nor appropriate for complex diseases,
he argued that his postulates were like a detective’s case, in which many small pieces of evidence can
substitute for a single convincing piece of evidence.
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4. Why do many correlations not show
causation? (Circle all correct.)
aa. There may be hidden variables
that explain the true causation.
bb. Correlation data comes from
poorly done experiments.
cc. Causation can only be shown by
Koch’s postulates.
dd. Correlation data is only one
line of evidence. Up to 8 other
criteria are necessary to show
causation.
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LESSON READINGS
DEFINITIONS OF TERMS
Underlying variables – also
known as “hidden” variables, are
factors that obscure a relationship
that is believed to be causal.
Figure 3: Koch’s postulates were the first way of showing that an agent is
responsible for causing disease. Unfortunately, Koch’s postulates are limited to
diseases caused by infectious agents, and can not be used for cancer.
Hill’s Postulates
When applied to smoking and lung cancer, Hill’s postulates strongly support causality, as seen below:
1. Plausibility — the link can be explained by biological explanations
2. Strength — a strong link is more likely to be causal than a weak one
3. Consistency — the link is observed repeatedly in different settings
4. Specificity — the link is a single factor causing a specific disease
5. Temporality — the factor exposure must precede onset of disease
6. Biological gradient — the extent of exposure should be proportional to risk of developing disease
7. Coherence — the relationship does not disagree with accepted scientific knowledge
8. Experiment — randomized intervention experiments in model animals produces disease
9. Analogy — a similar effect should be seen in other exposed populations/organs
Wo r k b o o k
Lesson 1.4
As we mentioned in the Metabolic Disease module, many correlations do not prove causation. For any
correlation, there are underlying, or “hidden” variables that may explain the relationship. For instance,
studies show that eating food coloring is correlated to hyperactivity, but that does not mean it is causative.
Foods that have food coloring typically may also have sugar, which is also correlated to hyperactivity, and
would be a hidden variable.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Meaningful relationship – a
type of relationship that cannot
be shown to be causal, but has
attempted to remove as many
hidden variables as possible.
The challenge of identifying causative agents
in cancer is that there is no ethical way to do
an interventional study on carcinogens causing
cancer in people. Therefore, Hill’s postulates is a
good substitute for identifying causal relationships
by identifying meaningful relationships. The
structure of the postulates is that by meeting more
criteria, you remove alternative explanations. If
for instance, scientists gave mice food coloring
agents (without sugar) and found that they
caused cancer, this would support the relationship
between food coloring and hyperactivity. The more
Hill’s postulates that are met, the more likely a
relationship is meaningful.
5. True or false: Lung cancer is caused
by genetics as well as smoking, so it
is not preventable.
aa. True.
bb. False.
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Figure 4: The time lag of 20 years
between cigarette consumption and
onset of lung cancer makes it difficult to
see the relationship between cigarettes
and lung cancer.
This history of how the association between
smoking and lung cancer was established also
reveals that lung cancer is a preventable disease.
We can dramatically reduce our risk of developing
lung cancer by not smoking. It is worth mentioning that a drop in lung cancer incidence occurred following
bans on smoking in public places like bars and restaurants that became commonplace during the 1990’s.
This approach towards removing the carcinogens in tobacco from our society is a good model for limiting
exposure to other carcinogens as a tool to prevent cancer.
Why is it so hard to prove something 'causes' cancer?
Let’s say hypothetically, that there is a contaminant in tobacco that causes cancer, there is no way of
separating that contaminant’s role in causing cancer from tobacco’s role in causing cancer. Nevertheless,
all tobacco products are shown by Hill’s postulates to be associated with cancer. Therefore, the
relationship is not causal, but meaningful.
Wo r k b o o k
Lesson 1.4
MC Questions:
Tobacco companies took advantage of this inability to prove causality in the 50's and 60's by releasing
ads distorting the evidence of a link between smoking and cancer. The relationship of smoking and lung
cancer was still in dispute for many people until the 1980s, where legal action against tobacco companies
forced them to reveal internal documents that proved that not only did tobacco companies know there was
a link between their product and cancer, but also that they suppressed research results demonstrating the
addictive properties of nicotine. The American public finally began to pay attention to the overwhelming
6. Why is it hard to prove something
causes cancer? (Circle all correct.)
aa. It is difficult to remove all hidden
variables.
bb. Companies have financial
interests in selling cancercausing products.
cc. People are unlikely to believe
something that is popular will
cause cancer.
dd. Scientists are not good at
communicating data to public.
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LESSON READINGS
scientific evidence, and the legal wrangling led to government restrictions on tobacco advertising and
taxes that collectively decreased the average consumption of cigarettes from 4,141 cigarettes per person
in the US in 1974 to 2,500 cigarettes consumed per person in the US in 1994.
DEFINITIONS OF TERMS
E-cigarette – an electronic
cigarette that is advertised as a
“healthy” alternative to smoking,
but involves inhaling a vapor
containing formaldehyde and
other known carcinogens.
Wo r k b o o k
Lesson 1.4
After these setbacks, the tobacco industry re-focused their efforts toward the developing world and
into non-cigarette tobacco usage. At the present time, 50% of men and 11% of women in developing
nations smoke cigarettes, and those numbers are increasing. Meanwhile, in the US, per capita cigarette
consumption continues to decrease from 2,076 in 2000 to 1,232 in 2011 (a 32.8% decrease), but per
capita cigar and loose leaf tobacco consumption has increased from 72 in 2000 to 142 in 2011 (a 96.9%
increase).
Figure 5: The time lag of 20 years between
cigarette consumption and onset of lung
cancer makes it difficult to see the relationship
between cigarettes and lung cancer.
Consumption of electronic cigarettes (or
e-cigarettes), also known as 'vaping'
because it involves inhalation of a chemical
vapor, is advertised as a healthy alternative
to smoking. However, the vaporized liquid
solution of e-cigarettes contains formaldehyde, a known carcinogen. Consumption of
e-cigarettes has increased exponentially, and
sales of e-cigarettes is expected to exceed
$10 billion by 2020. There is insufficient data
on the risk of consuming e-cigarettes to
lung or mouth cancers, so Hill’s postulates
cannot be determined for the relationship
between e-cigarettes and cancer. Nevertheless, there is concern for the consumption of
e-cigarettes, as they are unregulated by the
government, and children as young as 10 are
consuming these products.
MC Questions:
7. Which of the following helped reduce
the incidence of lung cancer in the
US? (Circle all correct.)
aa. Banning smoking from public
areas.
bb. Campaigns to raise awareness
of smoking and cancer.
cc. Tobacco companies making
safer cigarettes.
dd. Increased consumption of
e-cigarettes.
8. Why do people think e-cigarettes
may be hazardous to health? (Circle
all correct.)
aa. They meet all 9 Hill’s postulates
for cancer.
bb. They are smoked by the elderly.
cc. They contain known
carcinogens.
dd. They are made from tobacco.
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STUDENT RESPONSES
Look up online an agent that is said to 'cause' cancer. Based upon the article, how many postulates are met from the data
presented? Do you think this agent causes cancer? Why or why not?
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Wo r k b o o k
Lesson 1.4
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33
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.4
DEFINITION
Cases
The group within a case-control study that developed disease.
Case-control study
A study where patients with a disease and patients without disease are reviewed to identify patterns that
may have led to development of disease.
Controls
The group within a case-control study that did not develop disease.
E-cigarette
An electronic cigarette that is advertised as a “healthy” alternative to smoking, but involves inhaling a vapor
containing formaldehyde and other known carcinogens.
Hill’s Postulates
A list of epidemiological criteria that set the minimal evidence necessary to show causality.
Interventional study
A study where one group is given a treatment to evaluate the effect of that treatment on people.
Meaningful relationship
A type of relationship that cannot be shown to be causal, but has attempted to remove as many hidden
variables as possible as an attempt to show causality.
Over-reported
When survey respondents claim they partook of an activity more than they actually did.
Under-reported
When survey respondents claim they partook of an activity less than they actually did.
Underlying variables
Also known as “hidden” variables, are factors that obscure a relationship that is believed to be causal.
34
LESSON 1.5 WORKBOOK
How do we determine cancer risk?
DEFINITIONS OF TERMS
Risk factor – any agent that
increases the chance that someone will develop a disease.
For a complete list of defined
terms, see the Glossary.
The last lesson focused on how hard it is to definitively prove that a suspected
carcinogen actually causes cancer. This lesson looks at cancer from a different
perspective – how can we assess whether a specific behavior - like smoking
– increases the risk of developing cancer? Understanding how to assess risk is
critically important since it is clear that identifying a behavior as risky and then
eliminating it can be equivalent to avoiding a cancer-causing agent.
What are the major risk factors for cancer?
The previous lesson discussed how difficult it is to definitively prove that a substance is carcinogenic.
Because of these challenges most suspected carcinogens can only be categorized as risk factors. A risk
factor being any agent that increases the chance that someone will develop cancer. As seen in Figure 1,
the major risk factors of cancer are:
■■ Diet
■■ Tobacco
■■ Infections
■■ Obesity
■■ Others (Hormones, pollution, and radiation)
■■ Alcohol
■■ Genetics
Wo r k b o o k
Lesson 1.5
Surprisingly diet is the major risk factor for cancer, with
between 30-35% of all cancer being linked to diet. Diet
increases the risk of developing cancer directly and
indirectly: Directly, diets that are rich in red meats and
processed meats, and high in salt directly increase the
Figure 1: 95% of all cancers are caused
by environmental agents, chiefly diet and
smoking.
MC Questions:
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1. Which of the following is NOT a
major risk factor for cancer?
aa. Genetics;
bb. Infections;
cc. Tobacco products;
dd. Obesity.
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LESSON READINGS
risk of cancers of the digestive system: mouth, esophageal, stomach and bowel cancer. Conversely diets
rich in fruits, vegetables and fiber actually decrease the risk of these cancers. Diet plays an indirect role
in cancer by promoting obesity. Obesity in turn is often associated with abnormal hormone levels, which
also constitute a cancer risk.
It is estimated that 25-30% of all cancers are caused by smoking or exposure to tobacco smoke. While
we covered the link between tobacco and lung cancer in the previous lesson it is important to note that
smoking is a risk factor in a number of different cancers as well as lung cancer, the most prevalent being
mouth, esophagus, stomach, breast, and colon.
DEFINITIONS OF TERMS
Obesity – A medical condition
due to accumulation of excess fat
that can reduce life expectancy.
Hormone – an internal signal in
the bloodstream that regulates
cell and tissue growth and development.
Estrogen-like compounds –
chemicals that are commonly
found in plastics and that behave
like the hormone estrogen. A risk
factor for cancer.
Wo r k b o o k
Lesson 1.5
Infections are also responsible for causing 15-20% of all cancers; many different types are involved including stomach cancer, which is caused by the bacteria Helicobacter pylori, liver cancer which is caused by
Hepatitis B and C viruses (as well as the liver fluke parasite), and cervical and some oral cancers which
are caused by Human papillomavirus (HPV). Fortunately antibiotics against H. pylori and the liver fluke,
vaccines for HPV and Hepatiits B, and drugs to treat Hepatitis C all reduce the mortality associated with
these cancers.
Other environmental agents that promote cancer include hormones, pollution, and radiation. Chemicals
found in plastics behave like estrogen, a hormone that regulates cell growth. Overexposure to estrogen
promotes the risk of developing cancer. Pollution from coal, soot, and asbestos, typically from occupational exposure are cancer risk factors. Radiation exposure most typically occurs in the form of UV radiation
from the sun but may also be linked to occupational exposure.
Excessive alcohol intake is associated with increased risk of liver and
pancreatic cancer
To understand why the role of genetic inheritance in cancer risk is relatively small we need to consider
the two things that must have occurred to put the risk in place: First the DNA sequence of an important
gene, like a growth factor, must have been mutated in a specific way so as to interrupt its function.
Second that mutation must have occurred in the DNA of germ cells such as eggs and sperm so that the
mutation can be inherited. Nonetheless risk can be inherited: As we saw in lesson 1.3 mutations in the
retinoblastoma gene called Rb predispose to developing cancer of the retina of the eye (retinoblastoma)
as well as other types of cancers. Similarly, mutations in the BRCA1 gene predispose to risk for
developing breast, ovarian, prostate and pancreatic cancers. These issues will be addressed again in Unit
3.
MC Questions:
2. How is diet a risk factor for cancer?
(Circle all correct.)
aa. Diet can lead to obesity, which
promotes cancer.
bb. High meat diets increase cancer
risk.
cc. High fiber diets increase cancer
risk.
dd. Consumption of foods
containing estrogen-like
compounds can promote cancer.
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LESSON READINGS
As we saw in the last lesson, the ambiguities around causation as it relates to complex diseases like
cancer mean that it is usually not possible to determine unequivocally whether an agent truly “causes”
cancer. In contrast, establishing the risk associated with exposure to the suspected agent is much clearer.
Hill’s postulates don’t allow us to definitively prove whether or not cell phones cause brain cancer, but we
can easily calculate whether using cell phones increases the risk of developing brain cancer.
The ability to calculate whether a certain agent increases the risk of developing cancer allows us to start
to address critical questions such as: “What can I avoid in order to prevent cancer?”
DEFINITIONS OF TERMS
Relative risk – The extent to
which a risk factor is responsible
for causing disease in a population
Risk is generally calculated in one of two ways – as relative risk and as the odds ratio. They both
depend on the same concept – namely the likelihood that exposure to an agent will lead to disease.
The calculations are best understood using a simple example. The question being investigated is:
‘Does exposure to asbestos increase the risk of developing lung cancer?’. The researchers assembled
a population of people, some of whom were exposed to asbestos, some of whom weren’t. Then they
observed the population to figure out who developed lung cancer and who didn’t. The numbers are in
the table below. Even without a calculation it is evident that while the numbers of people who developed
lung cancer were similar, whether they were exposed to asbestos or not, the proportion of people who
developed lung cancer after asbestos exposure was much higher (1 in 1.6) compared with the group that
wasn’t exposed (1 in 7.6) Take a minute to make sure you understand how we got these numbers. Now
let’s use them to calculate relative risk:
Exposed to Asbestos
Odds ratio – The odds of a disease appearing in the population
after exposure to a risk factor.
Wo r k b o o k
Lesson 1.5
Not Exposed to Asbestos
Total
Lung Cancer
10
13
23
No Lung Cancer
152
747
899
Total
169
760
922
Relative Risk = (Exposed with lung cancer/Total Exposed) / (Not exposed with lung cancer/Total not
exposed)
Relative Risk = (10 / 162) / (13 / 760)
Relative Risk = 0.0617 / 0.0171
Relative Risk = 3.6
MC Questions:
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3. True or false: Relative risk is a
distinct calculation from odds ratio
and it is important to know the
difference between the two.
aa. True.
bb. False.
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LESSON READINGS
Another way to look at risk is with the odds ratio. Instead of comparing the people who got lung cancer
with the total in each group, it compares the people who got lung cancer in each group with the people
who didn’t get lung cancer in each group. Not surprisingly the numbers are slightly different:
Odds ratio =
(Exposed with cancer/Exposed and No cancer) / (Not exposed with cancer/Not exposed and no cancer)
Odds ratio = (10/152) / (13/747)
Odds ratio = 0.0657 / 0.0174
Odds ratio = 3.8
DEFINITIONS OF TERMS
Five-year survival rate – the
percent of people diagnosed with
the disease who are still alive
after five years.
Although both calculations are used for calculating risk, the relative risk is preferred over the odds ratio in
clinical studies, such as estimating cancer risk. This is because the odds ratio over-estimates risk unless
the disease is rare (you can substitute your own figures into the calculation to prove this point). Since the
definition of ‘rare’ is very subjective using the relative risk removes that concern.
But what does the number mean? If the relative risk or odds ratio is above 1, exposure to asbestos has
increased the risk of developing cancer. If the relative risk or odds ratio is 1, or close to 1 there is no
relationship between exposure to asbestos and cancer. But if the relative risk or odds ratio is below 1
exposure has actually protected against cancer. This clearly would not happen for asbestos, but for eating
fruits and vegetables the odds ratio of developing lung cancer is only 0.4, all other things being equal.
An asbestos worker might be tempted to think that (s)he could reduce their risk of developing lung cancer
by eating a healthier diet, but risk calculations can’t simply be added together in this way. While it is
certainly possible and often critically important to take the effect of more than one variable on an outcome
into consideration, the calculations are statistically very complex.
How do we measure cancer severity?
When considering whether to change a behavior, we might like to have more information in addition to
just the relative risk of developing the disease associated with it. For example, we might want to know
how severe the disease we are concerned about will be. The severity of a cancer is determined based on
three major characteristics: the number of people who will get it (incidence rate), the number of people
who will die (death rate), and the number of people who, having developed it, will still be alive five years
later (five-year survival rate).
Wo r k b o o k
Lesson 1.5
MC Questions:
4. Which of the following is not useful
to calculate an odds ratio for a risk
factor? (Circle all correct.)
aa. Number of people exposed to a
risk factor.
bb. Number of people who acquired
a disease.
cc. Number of people who died from
that disease.
dd. Number of people who received
a treatment.
5. True or false: A risk factor with an
odds ratio of 7 is very likely to be
responsible for causing cancer.
aa. True.
bb. False.
6. Which of the following is useful to
determine the severity of a type of
cancer?
aa. Incidence rate.
bb. Death rate.
cc. Five-year survival.
dd. All of the above.
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LESSON READINGS
Let’s look at the statistics for eight of the most common cancers arranged by incidence rate:
Incidence Rate Tumor Type (# w/ disease per 100K people)
465.2
All Types
DEFINITIONS OF TERMS
Incidence rate – the number of
people who develop the disease
per 100,000 people in the
population.
Death rate – the number of
people that die from the disease
per 100,000 people in the
population.
Death Rate
(# that die per 100K people)
Five-year
Survival Rate
178.7
65.2%
Prostate
69.4
9.1
98.9%
Breast
67.2
12.9
89.2%
Lung
62.6
50.6
15.7%
Colorectal
46.3
16.7
63.8%
Leukemia
12.5
7.1
53.2%
Pancreas
12.1
80.0
6.0%
Stomach
7.6
3.6
25.6%
Liver
7.5
5.5
16.6%
Both the incidence rate and the death rate are reported as the number of people per 100,000 (100K)
people in the population. So we can see that while prostate cancer is the most frequent cancer in the
population most people survive it. Prostate cancer is very slow growing and clinical symptoms usually
appear in the elderly. The five-year survival rate is also the highest for any of the cancers reported. All of
these considerations raise questions as to whether it is appropriate to treat prostate cancer aggressively,
especially if the treatment itself is very debilitating. We shall come back to this later.
Contrast prostate cancer with lung cancer. Lung cancer is less prevalent, but it has the highest death
rate and the number of people with lung cancer still alive after 5 years is low. This tells us that it would be
well worth changing any behavior that increases the risk of developing lung cancer (such as working with
asbestos, or smoking). Pancreatic cancer also has a poor prognosis. At least 80% of people with it will
die and fewer than 10% are alive after 5 years, indicating that good treatment is still lacking. Exposure to
carcinogens, like cigarette smoke, is also a significant risk factor for pancreatic cancer.
Wo r k b o o k
Lesson 1.5
The best way to assess disease severity is five-year survival, the final statistic on the table. While death
rates and incidence rates describe the extent that a cancer is present within a population, the five-year
survival rate provides an idea of how well the cancer can be managed, which is the ultimate goal. The
5 year survival with prostate and breast cancer is similar (98.9% vs 89.2%) but whereas many people
survive prostate cancer because it grows slowly, people survive breast cancer because detection and
treatment have improved considerably. Contrast these numbers with those surviving after pancreatic or
liver cancer, which have few effective treatments. In general cancers with five-year survival rates below
40% have poor treatment options. These therefore include lung, pancreas, liver and stomach. Brain
cancer also has poor survival but is not included on this chart.
MC Questions:
7. Based upon the table shown on the
left, which cancers are the most
severe?
aa. Breast and Prostate;
bb. Pancreas and Lung;
cc. Liver and Stomach;
dd. Leukemia and Colorectal.
8. Which of the following statistics
informs you that a cancer is easy to
treat? (Circle all correct.)
aa. Incidence Rate.
bb. Death Rate.
cc. Five-year survival.
dd. Odds Ratio.
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STUDENT RESPONSES
The odds ratio of artificial sweeteners (present in Diet sodas, like Coke and Pepsi) having a direct effect on various cancers
is 0.8. Would you avoid artificial sweeteners to reduce your risk of cancer? Why or why not? Is there another reason why you
might avoid artificial sweeteners, and might this be linked to cancer?
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Wo r k b o o k
Lesson 1.5
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40
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.5
DEFINITION
Death Rate
The number of people that die from the disease per 100,000 people in the population.
Estrogen-like compounds
Chemicals commonly found in plastics that behave like the hormone estrogen. A risk factor for cancer.
Five-year survival rate
The percent of people diagnosed with the disease who are still alive after five years.
Hormone
An internal signal in the bloodstream that regulates cell and tissue growth and development.
Incidence rate
The number of people who develop the disease per 100,000 people in the population.
Obesity
A medical condition due to accumulation of excess fat that can reduce life expectancy.
Odds ratio
The odds of a disease appearing in the population after exposure to a risk factor.
Relative risk
The extent to which a risk factor is responsible for causing disease in a population.
Risk factor
Any agent that increases the chance that someone will develop a disease.
41
Unit 2:
Unit 2: Introduction
Where are we heading?
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a 'normal' cell?
Unit 3: How does a normal cell become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How is cancer diagnosed and treated?
______________________________________
Unit 2 focuses on how normal cells behave in
their tissue communities and in particular their
vulnerabilities to mutation.
Lesson 2.1 explores what kinds of normal cells are particularly
vulnerable to cancer, and why. Lesson 2.2 investigates how a cell
controls its ability to replicate and how this control is disrupted in
cancer. Lesson 2.3 asks the question of how all cells can have the
same DNA but perform different functions. Lesson 2.4 deals with the
process of cell death and uses the apoptosis game to illustrate how
it is disrupted in cancer. Lesson 2.5 grapples with the idea of a cell
as part of a tissue community, exploring how normal cells depend on
each other and how they become isolated during cancer.
42
LESSON 2.1 WORKBOOK
Which cells are most vulnerable to
cancer, and why?
In the upcoming unit we will learn about how normal cells function, as a prelude
to learning about how these functions become abnormal during cancer. A useful
analogy is to think of each cell as a member of the community of cells that make
a tissue. In order for the tissue community to function properly each of its cell
members must communicate effectively with other community members in order
to perform its own specialized task. In this lesson we will define the cell community
we are most interested in – epithelial cells that are responsible for more than 80&
of all cancers.
MC Questions:
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The tissue community of cells
The complex function of the body as a whole is performed by individual organs, each of which plays a
particular role - such a respiration, digestion and reproduction. In turn each organ is composed of specific
components or tissues, which work as a community to perform that organ’s function. For example, the
respiratory system is composed of tissues that form the bronchi, which transfer air into and out of the body
cavity, and the lungs, where gas exchange into and out of the bloodstream take place. An organ’s tissues
are composed of individual cells each of which also has its own specialized function. But in order for the
tissue to function as a unit to drive organ function, each of the cells in the tissue must closely cooperate
with its neighbors. In the next few lessons we are going to focus on the tasks individual cells must perform
so that the community of cells as a whole can function. Just as individual members of any community are
born, make friends, grow up and get a job, and then grow old and die, so individual cells must accomplish
all of these tasks.
Wo r k b o o k
Lesson 2.1
1. Which is the smallest functional unit
of the body?
aa. System;
bb. Organ;
cc. Tissue; or
dd. Cell.
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LESSON READINGS
DEFINITIONS OF TERMS
Lumen – the inner space of a
tube.
Epithelial cells – closely packed
cells that separates the contents
of a lumen from the interior of the
body.
Parenchyma – the tissue of an
organ that is responsible for its
function.
Stroma – the connective tissue
framework of an organ that supports the epithelial layer of tissue.
Stromal cells – connective tissue cells and cells of the immune
system that are present in the
stroma that support epithelial cell
function.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
First of all we are going to identify a tissue community of cells to focus
on. The epithelium is a very good example. Our bodies are organized as a series of various “tubes” that connect organ to organ: For
example the digestive tract connects where we take food in via the
mouth to where waste is eliminated via the anus and passes through
the stomach and intestines, where food is absorbed. The blood and
lymph systems are a series of tubes that convey red and white blood
cells around the whole body. The liver and pancreas connect to each
other and to the intestines through tubes called bile ducts, that help
digest food. Finally the mammary glands in breasts secrete milk
through tubes called ducts.
Every organ’s system of tubes looks similar. The tube lining, called
Figure 1: Our body
the epithelium, is composed of a series of epithelial cells that are
can be viewed as a series
tightly attached to each other so they prevent substances within the
of tubes that move fluids
center of the tube (called its lumen) from leaking out. The epithelium
from organ to organ.
lining of the tubes performs different functions, depending on the
organ system it is associated with. For example some epithelia keep
the contents of the tube in the lumen – such as the bladder; some epithelia move contents out of the
lumen and into underlying blood vessels – such as the small intestine; and some epithelia move material
from the underlying tissue into the lumen of the tube – such as the mammary glands. In many cases an
organ’s tubes are its most important functional component. Because of this they are called the parenchyma of the organ (from the Greek ‘pour in’). Another important term in tube structure is the stroma
(from the Greek ‘mattress’) which is the supporting framework of the tissue underneath the epithelium that
helps keep the tubes intact.
Figure 2: Cross section of an epithelium in the esophagus. Epithelial cells
are in contact with the lumen of the
esophagus. They are supported by the
basement membrane and stroma, which
contains blood vessels.
We can therefore think of organs in general terms
having two tissue components: The epithelial
tube, consisting of individual epithelial cells tightly
attached to each other side to side to keep the
epithelium impermeable which often form the
functional parenchyma of the organ. Underneath
the epithelial lining is the supportive stroma, whose
main function is to support the epithelial tissue.
Within the stroma, blood vessels convey material to
and from the epithelial cells and provide nutrients
and signals for cell growth and survival. Lymph
vessels bring immune cells to the stroma to clear
MC Questions:
2. What are reasons that epithelial cells
are often the parenchyma tissue of
an organ? (Circle all correct.)
aa. They perform the function of the
organ.
bb. They are the fastest growing
cells.
cc. They are cells that form the
lining of the lumen.
dd. They are cells with best access
to blood and lymph.
3. What cells separate contents of the
lumen from the rest of the body?
aa. Basement membrane cells.
bb. Epithelial cells.
cc. Immune cells.
dd. Stromal Cells.
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LESSON READINGS
DEFINITIONS OF TERMS
Basement membrane – a thin
layer of connective tissue
underneath the epithelial tissue
layer.
Cuboidal epithelia – cubeshaped epithelial cells that
function for secretion.
Columnar epithelia – height
is much longer than their width.
These cells function for absorption of nutrients and secretion
and are found mostly in
the GI tract.
Transitional epithelia –
epithelial cells that can transition
in shape and size. These cells
are primarily found in the urinary
tract and prostate.
Wo r k b o o k
Lesson 2.1
away and dead cells and debris, as well as killing off pathogens that may have entered an organ.
MC Questions:
Separating the epithelial lining and the stroma is a layer of dense fibrous proteins called the basement
membrane. The basement membrane does not have the same structure as a cell membrane, rather
it is a dense layer of fibrous proteins that acts like ‘insulation’ for the epithelial lining of the tube to make
absolutely sure that the epithelium stays intact. The basement membrane is critically important for cancer,
as we will see.
4. Which of the following cell types
would likely be present in a tumor of
the mammary gland?
aa. Cuboidal epithelia;
bb. Columnar epithelia;
cc. Squamous epithelia; or
dd. Transitional epithelia.
Different epithelial cells have different functions
As we saw before, different organ tubes have
different functions, and this is reflected in
differences in the epithelial cells that line the
tubes. Organs like the stomach that secrete
gastric acid have different types of epithelia
lined than organs like the small intestine that
absorb nutrients. The skin too, has an epithelial lining, although in this case the ‘lumen’ is
the entire outside world. We can distinguish
four different kinds of epithelial cells:
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Figure 3: Cartoon depiction of four types of
epithelial cells. Each type has a distinct function.
■■ Cuboidal epithelia are shaped like
cubes. They are specialized for secretion so they are commonly found in organs where secretion is
important, such as salivary glands (saliva) and mammary glands (milk).
■■ Columnar epithelia are elongated and tightly packed. They are specialized for absorption and
secretion and can also handle harsh chemicals and mechanical stress so they are mostly found in
the digestive tract.
■■ Transitional epithelia vary in shape between cuboid and columnar. They are specialized to be
stretchy without breaking so they are mostly found in organs that need to expand and contract
like the urinary bladder, and gland ducts of the prostate. They often occur in layers to give more
mechanical strength.
■■ Squamous epithelia are flat and look like fish scales (squamous is Latin for ‘scale’). They are
specialized to be protective and are found where protection from mechanical forces is needed, such
as on the surface of the skin or lining blood vessels and the abdominal cavity Skin is composed of
squamous epithelium that protects us from the environment. Other squamous cells are found on
surfaces not typically exposed to the environment, such as blood vessels or the linings of internal
body cavities.
5. Which of the following cell types
would likely be found in a tumor of
the GI tract?
aa. Cuboidal epithelia;
bb. Columnar epithelia;
cc. Squamous epithelia; or
dd. Transitional epithelia.
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LESSON READINGS
Epithelial cells that are frequently exposed to stress or damage often form multiple layers, which allows for
cells on the outside to die without damaging inner lining of the tube. Multiple layered epithelia are found
in skin, hair, and nails, as well as in glands and organs that need to expand and contract. In contrast
epithelia involved in absorption in the digestive tract are specifically organized to take a substance up at
the lumen side, transport the material through the cell and release it at the other side (cells that secrete do
the opposite). These cells usually exist in a single layer to maintain the direction of transport.
Why epithelial cells are important in cancer.
DEFINITIONS OF TERMS
Squamous epithelia – flat,
scale-like, epithelial cells whose
chief function is protection from
the environment
In theory, any cell can develop into a tumor or cancer, but epithelial cell cancers are responsible for ~80%
of cancer-related deaths in the Western world (and ~70% in the developing world). Given what we now
know about how important epithelial cells are to the function of nearly every organ in the body, this should
not be at all surprising. If we describe a cancer by the type of cell that is affected, rather than the organ
the cancer derives from, it is clear why epithelial cell cancers are so common. This raises another point
also: It has now become clear that cancer of transitional epithelia in say kidney and prostate will have
a more in common with each other than a cancer of kidney epithelia compared with a cancer of kidney
stroma. As we understand more about how communities of cells in tissues are abnormal in cancers we
are moving away from describing cancers by the organ they occur in, to the tissue affected: carcinomas,
if the cancer originated from a squamous epithelial cell, or adenocarcinoma, if the cancer originated from
a columnar, cuboid or transitional epithelial cell.
Not all cancers originate from epithelial cells. The other major types of tumors originate from non-epithelial cells are:
Proliferate – the act of cells
dividing
■■ Sarcomas - these tumors originate from the cells found in stroma.
■■ Leukemias/Lymphomas – these tumors originate from white blood cells and cells of lymph nodes.
■■ Neuroectodermal tumors – these tumors originate from components of the nervous system.
■■ Melanomas – these tumors originate from the pigmented cells of the skin.
■■ Small-cell carcinomas – these tumors originate from a subset of cells found in the lung and cervix.
Wo r k b o o k
Lesson 2.1
Even this type of classification has problems because it is quite common for a single tumor to be
composed of multiple types of carcinomas. Furthermore an organ may contain both carcinomas and
sarcomas. For instance, more than 90% of all prostate cancers are adenocarcinoma, but the other 10%
can be other types of carcinomas or even sarcomas.
MC Questions:
6. Which of the following types of
tumors would be found in the
prostate gland? (Circle all correct.)
aa. Adenocarcinoma.
bb. Carcinoma.
cc. Melanoma.
dd. Sarcoma.
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7. Which of the following is most useful
to describe a cancer? (Circle all
correct.)
aa. The cell the cancer originates
from.
bb. The tissue the cancer originates
from.
cc. The organ the cancer originates
from.
dd. The system that cancer
originates from.
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LESSON READINGS
DEFINITIONS OF TERMS
Benign – a tumor located to the
epithelial cell layer
Malignant – a tumor that has
broken through the basement
membrane and entered the
stroma.
Carcinoma – general term for a
cancer of an epithelial cell.
Squamous cell carcinoma –
cancer of squamous epithelia
Adenocarcinoma – cancer of
columnar, cuboid, or transitional
epithelial cells.
Sarcoma – cancer of cells from
the stroma
Hyperproliferation – when cells
proliferate at abnormally high
levels.
Wo r k b o o k
Lesson 2.1
Why do most tumors originate in epithelial
cells? Again we need to look at epithelia
location and function. As the barrier
between the outside world and the inside
they are the first line of defense against
damaging environmental factors. We
learned in the Infectious Disease module
that epithelia are exposed to infectious
agents, like viruses and bacteria. They are
also damaged by physical irritation, chemiFigure 4: Cells that proliferate normally have
cals and even hormones. When epithelial
a defined shape and size. Hyperproliferating
cells get damaged and die, others must
cells grow rapidly and look abnormal.
grow to replace them. The more frequently
they are damaged the more rapid the
replication. The more a cell proliferates, the more likely it is to acquire mutations that will lead to tumor
formation. This phenomenon is called hyperproliferation. Another name for a substance that damages a
cell making it hyperproliferate and leading to tumor formation is a carcinogen.
Tumors at the interface between the outside world and the body are, as epithelial tumors are, more likely
to be detected than tumors buried within the stroma, which may not produce symptoms until they are very
large. In contrast, carcinomas seen on the skin, or in the lung, or GI tract will produce obvious symptoms. It is possible that cancers exist in other parts of the body that we never observe and never cause
symptoms of disease. As we will see later on, the cell(s) that form the tumor plays an important part in how
a tumor develops, what type of cancer will be produced, and what the disease outcome of that cancer will
be.
MC Questions:
8. Why do most cancers originate from
epithelial cells? (Circle all correct.)
aa. Epithelial cells are the most
exposed to carcinogens.
bb. Epithelial cells hyperproliferate
more than other cells.
cc. Epithelial cells break through
basement membrane.
dd. Epithelial cells are cells most
likely to produce symptoms.
9. Which of the following is the step
that initially differentiates a cancer
from a tumor?
aa. Hyperproliferation of cells;
bb. Formation of a tumor;
cc. Tumor breaks through basement
membrane; or
dd. Tumor enters blood stream.
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STUDENT RESPONSES
Describe 2 reasons why you think 80% of cancers originate from epithelial cells.
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Wo r k b o o k
Lesson 2.1
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48
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
DEFINITION
Adenocarcinoma
Cancer of columnar, cuboid, or transitional epithelial cells.
Basement membrane
A thin layer of connective tissue that underlines the epithelial tissue layer.
Carcinoma
General term for a cancer of the epithelial cell.
Columnar epithelia
Cells whose height is much longer than their width. These cells function for absorption of nutrients and
secretion and are found mostly in the GI tract.
Cuboidal epithelia
Cube-shaped epithelial cells that function for secretion.
Epithelial cells
One of many closely packed cells that separates the contents of a lumen from the rest of the body.
Hyperproliferation
When cells proliferate at abnormally high levels.
Lumen
The inner space of a cavity, vessel, intestine, or other tube.
Parenchyma
The tissue of the organ that is responsible for the function of that organ.
Proliferate
The act of cells dividing.
Sarcoma
Cancer of cells from the stroma.
Squamous epithelia
Flat, scale-like, epithelial cells whose chief function is protection from the environment.
Stroma
The connective tissue framework of an organ that supports the epithelial layer of tissue.
Stromal cells
Connective tissue cells and cells of the immune system that are present in the stroma that support epithelial
cell function.
Transitional epithelia
Epithelial cells that can transition in shape and size. These cells are primarily found in the urinary tract and
prostate.
49
LESSON 2.2 WORKBOOK
How is a cell born?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
During the process of mitosis a cell replicate its DNA to create an identical ‘sister’
cell. But cells spend very little of their life cycle in mitosis; most time is spent waiting
for signals from the outside to tell the cell mitosis is necessary either to replace a
dead cell or make the tissue larger. This lesson introduces the concept of the cell’s
life cycle, describes the different phases of the cell cycle and introduces the driver
proteins that respond to signals and control progression to mitosis. When these
driver proteins become mutated so cells hyperproliferate, a tumor may form.
Why should I care about cancer?
Cell cycle – the progression of
events that prepares a cell to
replicate, and then leads to division into two daughter cells.
Mitosis – the phase of the cell
cycle in which one cell divides
into two identical daughter cells.
Wo r k b o o k
Lesson 2.2
How are cells born? Rudolph
Virchow, who we learned about in
Unit 1, put it most succinctly when
he stated, “Every cell comes from
another cell”. This means that
each cell contains a mechanism
that allows it to give birth to an
identical sibling. You have probably
learned about how the process
Figure 1: The basic steps of mitosis involve replicaof mitosis allows a cell that has
tion of DNA, then separation into two daughter cells.
duplicated its DNA to separate
that DNA into two identical cells.
But there is more to giving birth than simply the process of mitosis. Cells usually only divide when there
is a reason to do so – either because the tissue of as a whole is growing, or because a cell has died and
needs to be replaced. When a cell divides is so tightly controlled that cells spend most of their time waiting
for and responding to signals from the environment that tell them mitosis is necessary, than in the process
of mitosis itself.
MC Questions:
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1. What happens once the cell cycle is
completed?
aa. The cell dies.
bb. The cell is ready for mitosis.
cc. Two daughter cells are made.
dd. The cell has replicated its DNA.
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LESSON READINGS
We can think of the cycle of waiting and then responding to signals followed by mitosis followed by waiting
and responding again as analogous to the circle of life, and indeed it is called the cell cycle. As each cell
progresses through the cell cycle, it changes to reflect which stage of the cycle it is in. These stages can
be grouped into 4 major phases of development, which each cell must pass through before it is ready to
produce offspring during mitosis. These stages (or phases) of the cell cycle are:
■■ Gap 1 (G1) phase – the receives information from the environment that mitosis is required, and
begins to prepare
■■ Synthesis (S) phase – the cell duplicates its DNA (called its genome) in preparation for replication.
DEFINITIONS OF TERMS
■■ Gap 2 (G2) phase – the cell prepares the materials it needs for the process of mitosis.
■■ Mitosis (M) phase – the cell actually divides.
Interphase – The phases of
the cell cycle in which the cell is
preparing to undergo mitosis by
replicating its DNA and making
the proteins necessary to make
another cell.
Mitosis – the phase of the cell
cycle in which one cell divides
into two identical daughter cells.
Wo r k b o o k
Lesson 2.2
The first three phases of the cell cycle (G1,
S and G2) are collectively called interphase, which is a general term to indicate
that the cell is preparing for mitosis but not
actually dividing yet. Mitosis (also called M
phase) is when the cell actually divides. First
level biology courses tend to focus on the
process of mitosis and ignore what happens
during interphase, but interphase is critically
important because it ensures that mitosis
only takes place when and where it is
Figure 2: Cartoon depiction of the cell cycle,
needed. In fact mitosis is actually the shortInterphase is broken down into G1, S, and G2
est phase of the cell cycle and by the time
phases, followed by the process of mitosis,
which occurs in M phase.
the cell has reached the M phase, mitosis is
practically inevitable. Here we will be focusing on what happens during interphase
because losing the ability to regulate when mitosis takes place is one of the key hallmarks of cancer.
In the last lesson we emphasized that tissue is a community of cells that are sensitive to external events
such as infection and damage. Cells in the tissue community are in constant communication (we will learn
how in the next lesson) telling each other how to respond to these events to preserve tissue function.
Not surprisingly, one event that needs a quick response is when a cell gets damaged or dies, because
another cell needs to be generated to take its place. If we think back to the epithelia we studied yesterday,
if one epithelium cell dies it is crucial to replace it quickly so the lining of the tube doesn’t leak. In this case
MC Questions:
2. Which of the following is the shortest
phase of mitosis?
aa. Gap 1 phase;
bb. Synthesis phase;
cc. Gap 2 phase; or
dd. Mitosis phase.
3. Why would cells need mitogens
to promote cell growth? (Circle all
correct.)
aa. Surrounding cells are secreting
anti-mitogens.
bb. There is a need for cells to
replicate.
cc. There are too many cells in the
tissue.
dd. Mitogens promote entry into cell
cycle.
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LESSON READINGS
surrounding cells send each other signals that they need to replicate, and once the hole is plugged, they
send other signals to stop replication carrying on. Signals that promote replication (pro-growth signals)
are called mitogens. Mitogens tell cells that they should prepare for mitosis. Signals that stop replication
(anti-growth signals) are called anti-mitogens. In a mature normal tissue there will be more anti-mitogens
than mitogens. When mitosis is needed, more mitogens will be produced.
Progressing through the cell cycle: driver proteins
DEFINITIONS OF TERMS
Mitogen – a chemical signal that
tells the cell to undergo mitosis.
Anti-mitogen – a chemical
signal that tells the cell not to
undergo mitosis
Driver proteins – an intracellular protein that promotes the
progression of the cell cycle.
Cyclins – the driver proteins that
control the progression of the cell
cycle.
R point – the point in the G1
phase of the cell cycle after which
a cell no longer needs an external
signal to progress to mitosis.
Wo r k b o o k
Lesson 2.2
Another way to think of the cell cycle like a clock with gears that make the hands move. The roles of
moving gears in the cell are played by a family of proteins called the cyclins. The cyclins act as driver
proteins, because like a driver drives a car, cyclin proteins drive the cell cycle forward like gears in a
clock. Each phase of the cell cycle has its own cyclin proteins that act as gears to drive the cell through
that phase and onto the next.
■■ The G1 phase driver is called Cyclin D. Mitogens cause the cell to make cyclin D. Once enough
Cyclin D has been made the cell starts making the proteins necessary for S phase, including the first
S phase driver.
■■ The first S phase driver is called Cyclin E. Cyclin E tells the cell to make the proteins it needs to
replicate DNA as well as the second S phase driver.
■■ The second S phase driver is called Cyclin A. Cyclin A responds to successful completion of DNA
replication by telling the cells to make the proteins it needs for th G2 phase.
■■ The G2 phase and the mitosis driver is called Cyclin B. Cyclin B tells the cell to make the proteins it
needs to complete mitosis and responds to signals that mitosis has been successful.
Where do mitogens and anti-mitogens come in? Cells are responsive to mitogens and anti-mitogens at
the G1 phase of the cell cycle. At the end of the G1 phase the restriction point (or R point) marks the end
of the cell’s sensitivity to these signals. When the cell cycle reaches the R point the cell’s DNA is checked
for damage. If the DNA is undamaged the first S phase driver will be made and then the cell can progress
through the rest of the cell cycle irrespective of what signals are present in the environment. If the cell’s
DNA is damaged, the cell will spend time repairing it before passing through the R point and only start
making the first S phase driver once repair is complete. If the DNA is too damaged to repair, the cell will
essentially commit suicide (we will learn how later). The R point is like a ‘point of no return.
MC Questions:
4. How do cyclins promote progression
of the cell cycle? (Circle all correct.)
aa. Repair DNA during replication.
bb. Activate expression of proteins
necessary for next phase of cell
cycle.
cc. Promote expression of Rb.
dd. Promote expression of INK
proteins.
5. Which of the following mitogens are
activated by mitogen signals?
aa. Cyclin A.
bb. Cyclin B.
cc. Cyclin D.
dd. Cyclin E.
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52
LESSON READINGS
DEFINITIONS OF TERMS
Hyperproliferation – when cells
proliferate at abnormally high
levels.
Checkpoints – the transition
points between different phases
of the cell cycle where the cell
evaluates whether preparation for
replication is occurring properly.
In Figure 3 we have cut the circle seen
in Figure 2 after the mitosis phase so we
can more easily see how the amount
(level) of each driver rises and falls as the
cell moves round the cell cycle. As we
can see it is like a relay race: as the level
of one driver falls, another driver rises to
take over and drive the next phase of the
cell cycle.
Figure 3: Levels of cyclin protein within the cell
change as the cell progresses through the cell
cycle.
You may wonder – why does the cell
need so many proteins to move it through
the cell cycle? Why not just have cyclin D
do everything? Well, the more steps the cell cycle is broken down into, the more different kinds of control
can be exerted. For instance, the cell won’t want to replicate if its DNA is damaged, so having the first
S phase driver (Cyclin E) only made once the DNA has been repaired in G1 means that the cell won’t
produce damaged offspring.
Conversely, if the levels of the cyclins aren’t regulated properly so they are high all the time, the cell
would replicate constantly. Normally cells in the tissue community release anti-mitogen signals once
their numbers are at the correct levels. Cells that don’t respond to those signals and continue to replicate
irrespective of whether their DNA is damaged are said to be hyperproliferating as we saw yesterday.
Hyperproliferation is a hallmark of tumor formation.
Preventing errors in cell replication.
We have learned how dividing the cell cycle into different phases provides more opportunities for control,
We also learned that the cell cycle is like a relay race in which the levels of the driver proteins determine
the ‘hand off’ to the next phase. These hand-off points are critically important because they act as
checkpoints – where decisions are made about whether the cell is in good enough shape to move on to
the next phase of the cell cycle. The important checkpoint controls in the cell cycle occur at:
Wo r k b o o k
Lesson 2.2
■■ The transition between G1 » S aka the R point. The transition will not occur if the cell’s DNA is
damaged.
■■ The transition between S » G2. The transition will not occur if DNA has become damaged during
replication or if replication has not been completed.
MC Questions:
6. Which is a way that cells regulate cell
proliferation? (Circle all correct.)
aa. Responding to external growth
and anti-growth signals.
bb. Sequential activity of cyclins.
cc. Limiting the speed of DNA
replication.
dd. Activation of hyperproliferation.
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7. True or False: Surrounding cells
have no influence on whether a cell
enters the cell cycle or not.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
INK proteins – a family of
proteins that specifically inhibit
the activity of cyclin proteins and
prevent progression of the cell
through the cell cycle.
Retinoblastoma – a protein that
prevents entry into the cell cycle
until the cell is ready to replicate
and divide.
DNA repair proteins – proteins
that are responsible for identifying and correcting damage that
occurs to DNA.
Wo r k b o o k
Lesson 2.2
■■ The transition between G2 » M. The transition will not occur If DNA replication has not been
completed.
MC Questions:
■■ During mitosis. Mitosis will not occur if the chromosomes are not properly aligned.
8. Which of the following checkpoints
are sensitive to external anti-growth
signals? (Circle all correct.)
aa. G1 » S
bb. S » G2
cc. G2 » M
dd. Mitosis
These checkpoints are enforced by specific checkpoint proteins, which act like brakes on the drivers and
prevent progression to the next step of the cell cycle. There are two major types of checkpoint proteins
that work slightly differently INK proteins work at all the checkpoints whereas the retinoblastoma
protein (Rb) works specifically at the R point. The checkpoint proteins play an important role in preventing hyperproliferation and controlling the progression of the cell cycle. If cyclins are driver proteins, these
proteins are the brakes.
The brake proteins at each checkpoint are called INKs. The INK proteins at each checkpoint are different,
but they work in the same way: They recognize DNA damage stop the cell progressing to the next phase
of the cell cyclin by inhibiting the hand-off to the next cyclin. Once the hand-off is blocked, proteins responsible for repairing DNA damage, called DNA repair proteins, can do their maintenance work. Then the
successful repair is sensed and the INKs go away.
The R point brake protein is called Retinoblastoma (Rb). Rb is often called the ‘Gatekeeper’ of the cell
cycle because the R point is like a gate – any cell that enters the gate will go straight through the cell
cycle. At the beginning of this lesson we noted that in mature normal tissues cells the gate is shut - cells
aren’t dividing. Rb is like the latch on the gate and the signals that keep the latch down are anti-mitogens.
High enough levels of mitogens can overcome the effects of the anti-mitogens and allow the latch to open.
But if DNA is damaged, INKs will prevent the cell passing through the R point gate until DNA is repaired.
DNA repair proteins are not completely successful but only a few random mutations escape control when
a cell divides (~75 mutations out of 6.4 billion nucleotides at each cell duplication). On the other hand, if
DNA damage is irreparable, this will lead to cell death (more on that later in this Unit).
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9. Which of the following is an outcome
of DNA damage to the cell? (Circle all
correct.)
aa. Activation of INK proteins.
bb. Activation of mitogen proteins.
cc. Activation of cyclins.
dd. Activation of DNA repair
proteins.
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STUDENT RESPONSES
Give 2-3 changes to the control of cellular replication that could occur in a cell that results in hyperproliferation.
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Wo r k b o o k
Lesson 2.2
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55
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.2
DEFINITION
Anti-mitogen
A chemical signal that tells the cell not to undergo mitosis.
Cell cycle
The progression of events that prepares a cell to replicate, and then leads to division into two daughter cells.
Checkpoints
The transition points between different phases of the cell cycle where the cell evaluates whether preparation
for replication is occurring properly.
Cyclins
A family of proteins that control the progression of the cell cycle.
DNA repair proteins
Proteins that are responsible for identifying and correcting damage that occurs to DNA.
Driver proteins
An intracellular protein that promotes the progression of the cell cycle.
Hyperproliferation
When cells proliferate at abnormally high levels.
INK proteins
A family of proteins that specifically inhibit the activity of cyclin proteins and prevent progression of the cell
through the cell cycle.
Interphase
The phases of the cell cycle in which the cell is preparing to undergo mitosis by replicating its DNA and
making the proteins necessary to make another cell.
Mitogen
A chemical signal that tells the cell to undergo mitosis.
Mitosis
The phase of the cell cycle in which one cell divides into two identical daughter cells.
Retinoblastoma
A protein that prevents entry into the cell cycle until the cell is ready to replicate and divide.
R point
The point in the G1 phase of the cell cycle after which a cell no longer needs an external signal to progress
to mitosis.
56
LESSON 2.3 WORKBOOK
How do cells communicate
information?
In the previous lesson we learned that normal cells replicate only when their cell
community signals them to do so. Communication among and within in cells is
critically important for them to function within their community. This lesson uses
as an example the healing response a tissue community mounts when it is
wounded to investigate how a cell takes an external signal and converts it to the
changes in cellular behavior that lead to cell proliferation.
Communication among cells
No cell in a community of tissues exists in isolation. For a tissue to function coherently its members are in
constant communication among themselves. An excellent example of this principle is the changes that a
tissue undergoes in response to a challenge such as a wound. The cellular communication that leads to
wound healing has been best studied in skin tissues. If a cut, scrape or other type of wound to the skin is
deep enough to break the endothelial lining of blood vessels (remember the blood vessel endothelium is
the epithelial lining of the tubes of the circulatory and lymphatic system) blood cells called platelets exit the
damaged blood vessel and flood the wound area. Once the platelets enter the wound area they secrete
proteins that signal the blood in the area to clot and form a scab that protects the wound from the environment that could lead to infections.
Wo r k b o o k
Lesson 2.3
Platelets also secrete proteins that signal undamaged cells in both the epithelia and stroma to start
proliferating and differentiating. The epithelial cells need to proliferate in order to replace cells that were
damaged by the wound, and proliferation and differentiation of the stroma is also needed to repair the
wound efficiently. The immune system also becomes involved: Immune cells enter the site of the wound
attracted by signals released by the damaged cells and they in turn signal other dealt with as well as the
epithelial and stromal cells in the area to promote growth and differentiation.
MC Questions:
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1. True or False: Cells signal only when
they want other cells to change
behavior.
aa. True.
bb. False.
57
LESSON READINGS
DEFINITIONS OF TERMS
Ligand – a signaling molecule
that binds a receptor on a cell
membrane.
Receptor – a cell membrane
protein that interacts with
external ligands and is modified
in response. The modification
activates internal transduction
proteins.
Paracrine signaling – signaling
between neighboring cells.
At this point it would be fair
to say that the wound area
resembles the construction
site in the middle of the day
with all the many different
construction workers yelling
instructions together and
moving materials around until
the job is finished. Just like
on a construction site where
every worker has their own
task and follows a specific
set of instructions, all the cells
involved in reconstructing a
new epithelial sheet also have
their own tasks.
Figure 1: At the site of the wound, epithelial cells
must lose the adherence dependent growth in order to
migrate and grow into the site of the wound. Once the
tissue has been repaired, the cells must stop growing,
which occurs through contact inhibition of growth.
At the beginning of repair, growth and differentiation are promoted; when repair is complete, both growth
and differentiation are switched off. The key to these processes occurring in a timely fashion is the
concept of ligands and receptors. Ligands are molecules that constitute the signals one cell uses to
communicate with each another, receptors are molecules, usually proteins, on the surface of the recipient cell that recognize the shape of the signaling ligand. The key is specificity. The signals platelets use to
communicate with epithelial cells are different from the signals they use to communicate with stromal cells.
Likewise the receptors on epithelial that recognize its signaling ligand will be different from the receptors
on the stromal cell uses to recognize its signaling ligand. Similarly, the signaling ligand and receptor that
are used to promote cell proliferation will be different from the signaling ligand and receptor that are used
to stop cell proliferation once the wound has healed.
This general principle of one cell providing a specific signaling ligand and another cell providing a receptor
that is specific for that ligand underlies all communication between cells whether they are next to each
other in the epithelium or distant from each other, maybe even in a distant organ. In fact we can define
three types of signaling in this way.
Wo r k b o o k
Lesson 2.3
1. When neighboring cells communicate with each other, this is called paracrine signaling. An
example of paracrine signaling is the communication between platelets and stromal cells in a wound.
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LESSON READINGS
2. When distant cells communicate with each other this is called endocrine signaling. An example of
endocrine signaling is the hormones released into the blood that can signal cells in a distant organ,
such as when the intestine releases hormones that tell the brain to change eating behaviors.
3. When cells communicate with themselves this is called autocrine signaling. In this case a cell
releases a signal and the receptor is on the same cell. An example of autocrine signaling occurs
when neurons release a neurotransmitter which is recognized by a receptor on the same cell that
turns off the release.
DEFINITIONS OF TERMS
Endocrine signaling – signaling
between distant cells in which the
signaling ligand travels through
the bloodstream.
Autocrine signaling – signaling
in which a cell communicates
with itself by releasing a ligand
that interacts with a receptor on
the cell surface.
Most cells are able to participate
in more than one type of signaling
and some cells can participate in
all three. Under normal circumstances these signals are telling
the cell to essentially ‘keep up
the good work’ - that is maintain
the status quo so tissue function
can continue as normal. But once
an event like a wound occurs the
cells in the tissue need to swing
Figure 2: Three types of signaling: paracrine,
into action to modify their behavautocrine, and endocrine.
ior, so the challenge becomes
how to receive, interpret and
distinguish between a complex
array of signals that may be telling them to divide (or stop dividing when healing is complete) differentiate
(or stop differentiating if healing is complete and survive (or die if it is too damaged to be repaired).
How do cells respond to, and distinguish between extracellular signals?
Wo r k b o o k
Lesson 2.3
We can think of the cell membrane like the walls of a castle protecting the interior cytoplasm. Each receptor on the surface of the cell acts like a castle tower guard. When a guard receives a signal from outside
the castle (s)he needs to convey the information to the king who sits in the nucleus waiting to respond.
How the king responds will depend on what information he gets from the guard. If a member of his family
has arrived he might prepare a banquet, but if an enemy army has appeared he is more likely to set up
the boiling oil. But the guards on the castle tower cannot leave their posts to tell the king what’s happening
directly. They must remain on the walls so they can be vigilant about incoming information. They solve this
problem by enlisting pages whose job it is to shuttle information from the castle walls (the cell membrane)
to the king in the nucleus so the king can respond.
MC Questions:
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2. What type of signaling occurs
between nearby cells?
aa. Autocrine signaling;
bb. Endocrine signaling;
cc. Exocrine signaling;
dd. Paracrine signaling.
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3. Which of the following signals
instructs a cell on how to change its
behavior? (Circle all correct.)
aa. Die.
bb. Don’t grow.
cc. Grow.
dd. Specialize.
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59
LESSON READINGS
In the cell the role of the pages is played by many different proteins we have called ‘transduction
proteins’. The main task of transduction proteins, like the pages in our analogy, is to traverse the cytoplasm to convey information from the membrane to the nucleus. Transduction proteins therefore behave
as intracellular signals. When the receptor at the membrane interacts with a ligand its shape changes in
response and the shape change travels from the outside of the membrane, where the ligand has bound to
the inside, where the transduction proteins are. The transduction proteins become activated in response
to the changed receptor and in turn convey the signal to the nucleus.
DEFINITIONS OF TERMS
Transduction proteins – cytoplasmic proteins that respond
to changes in a receptor and
then spread the responses in the
cytoplasm ultimately affecting
gene transcription.
Transcription factors – proteins
that are responsible for altering
the expression of genes.
Conveying the signal across the cytoplasm may require several steps. Once the transduction protein
signal has reached the nucleus it needs to interact with a receptor at the nucleus in a similar way that the
extracellular signaling ligand interacted with an extracellular receptor to change its behavior. In the case of
the intracellular transduction protein signal, the receptor at the nucleus is more often than not a transcription factor. Transcription factors respond to intracellular signals by either turning gene expression on or
off. We can imagine how an extracellular signal telling a cell to proliferate might interact with an extracellular receptor specific for that signal and then activate intracellular transduction protein signals. The
intracellular transduction protein signals might then activate transcription factors that would turn on genes
for proteins that would drive the cell cycle, like the cyclins we learned about in the last lesson.
A single receptor can activate many kinds of transduction proteins and they in turn can activate many
different transcription factors which switch many genes on or off. This is called a signaling cascade.
Returning to our castle analogy, the banquet the king makes to welcome his aunt will have many courses.
Or, in the context of the cell cycle, there are several phases, each with its own driver.
Signaling cascade – the series
of sequential events that amplify
the signal that occurs when a
ligand binds a receptor.
Wo r k b o o k
Lesson 2.3
Figure 3: Signal binding receptor activates
multiple transduction proteins (T.P.), which can
either activate other transduction proteins
(T.P.) or transcription factors (T.F.). Activation of
transcription factors changes protein expression in
the cell, which may change cell behavior.
At any given moment in any given cell
many signaling cascades are active
at any one time. This makes thinking
about what the effect of signaling
will be very complex. It is tempting to
draw diagrams like the one in Figure
3 that lists all the cascades activated
by different receptors and then tries
to figure out what the end result will
be at the nucleus. But the problem
is complicated because some of the
cascades can activate each other and
yet others compete with each other. It
is simply not possible to understand
what will happen by making drawings
like this.
MC Questions:
4. True or False: A cell receives one
type of signal at a time.
aa. True.
bb. False.
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5. Which of the following proteins
are responsible for spreading and
amplifying a signal within the cell?
aa. Ligand;
bb. Receptor;
cc. Transcription factor;
dd. Transduction protein.
6. Which of the following accurately
describe cell signaling? (Circle all
correct.)
aa. One ligand binding to a receptor
can activate many transduction
proteins.
bb. One ligand binding to a
receptor can only activate one
transduction protein.
cc. Different signals can activate the
same transduction protein.
dd. Different signals can activate
different transduction proteins.
60
LESSON READINGS
The simulation we will do in the lesson today attempts to deal with this problem by asking the computer to
work out the end result once all the input parameters are in place.
Cell signaling in wound healing
DEFINITIONS OF TERMS
Adherence-independent
growth – the property of
epithelial cells that allows them
to proliferate once they have
detached from the basement
membrane.
Contact inhibition – the
property of epithelial cells that
prevents them from proliferating if
they are physically touching each
other.
Cadherins – surface proteins of
epithelial cells that bind cadherins
on other epithelial cells they are
touching to activate the contact
inhibition signaling pathway.
Wo r k b o o k
Lesson 2.3
We can apply what we have learned about the principles of cell signaling to the response of skin epithelial
cells to a wound. The task of the epithelial cells is to repair the wound by reconstructing the damaged
epithelial sheet. To do this epithelial cells that have remained undamaged must begin to proliferate. But
before they can proliferate they have to inactivate two signaling mechanisms that prevent cells in normal
epithelia from dividing.
1. The first signaling mechanism comes from the basement membrane. As we saw in Lesson 2.1,
epithelial are normally attached to the basement membrane, which provides structural support.
But the basement membrane also provides signals to the epithelia which stop them dividing. So
the epithelial cell detaches from the basement membrane to inactivate those signals. This allows
adherence-independent growth.
2. The second signaling
mechanism comes from
the contact between one
epithelial cell and another.
Again as we saw in Lesson
2.1, tight contact between
epithelial cells is necessary
to stop the epithelium leaking, but it also prevents the
cells dividing: A protein on
the surface of epithelial cells
called cadherin will activate
another cadherin on a
second epithelial cell when
they are attached to each
other causing contact inhibition of cell proliferation. So
the epithelial cells detach
from each other to inactivate
those signals. This allows
proliferation to occur.
MC Questions:
7. True or False: Signaling can
inactivate transduction proteins as
well as activate them.
aa. True.
bb. False.
8. Which cellular process is
responsible for ending the wound
healing process for epithelial cells?
aa. Adherence dependent growth;
bb. Contact inhibition;
cc. Stromal cell growth;
dd. Stromal cell specialization.
9. How do cancer cells change cell
signaling within a tissue to promote
their growth? (Circle all correct.)
aa. Cancer cells make signals for
themselves.
bb. Cancer cells force surrounding
normal cells to change their
signaling.
cc. Cancer cells shut off all
signaling pathways.
dd. Cancer cells don’t make
receptors that bind death/don’t
grow signals.
Figure 4: Signaling pathways occur through different
signals binding receptors, which interact with various
transduction proteins that interact with various
transcription factors.
61
LESSON READINGS
Cancer cells are isolated from the tissue community
One trait that tumor cells acquire early in their development is that they lose the ability to respond to the
paracrine signals from surrounding tissue and endocrine signals from distant sites that normally prevent
proliferation while at the same time increasing autocrine signaling pathway that promote their own growth
and migration. This go-it-alone attitude is a hallmark of cancer, and indicates that tumor cells stop being
part of the community of cells in a tissue.
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.3
The kind of autocrine signals cancer cells (particularly breast, prostate, colon, and lung) release are the
same as those used during wound healing to promote growth and migration. Moreover, recent research
has shown that cancer cells also stimulate the normal surrounding tissue to behave as though a wound
had occurred, and to secrete the signals that promote wound healing. In this way cancer cells signal to
surrounding tissue to promote their own agenda.
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62
STUDENT RESPONSES
Explain how wound healing is a coordinated process of signaling in normal cells, but also used to promote the growth and
spread of cancer cells.
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Wo r k b o o k
Lesson 2.3
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63
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.3
DEFINITION
Adherence-dependent
growth
The property of epithelial cells that allows them to proliferate once they have detached from the basement
membrane.
Autocrine signaling
Signaling in which a cell communicates with itself by releasing a ligand that interacts with a receptor on the
cell surface.
Cadherins
Surface proteins of epithelial cells that bind cadherins on other epithelial cells they are touching to activate
the contact inhibition signaling pathway.
Contact inhibition
The property of epithelial cells that prevents them from proliferating if they are physically touching each other.
Endocrine signaling
Signaling between distant cells in which the signaling ligand travels through the bloodstream.
Ligand
A signaling molecule that binds a receptor on a cell membrane.
Paracrine signaling
Signaling between neighboring cells.
Receptor
A cell membrane protein that interacts with external ligands and is modified in response. The modification
activates internal transduction proteins.
Signaling cascade
The series of sequential events that amplify the signal that occurs when a ligand binds a receptor.
Transcription factors
Proteins that are responsible for altering the expression of genes.
Transduction proteins
Cytoplasmic proteins that respond to changes in a receptor and then spread the responses in the cytoplasm
ultimately affecting gene transcription.
64
LESSON 2.4 WORKBOOK
How does a cell specialize?
DEFINITIONS OF TERMS
Cell differentiation – the process of cellular specialization.
Stem cells – a type of cell that
can differentiate into many different cell types.
Embryonic stem (ES) cells –
cells from an early stage in human development that can form
any type of cell in the body.
Self-renewal – the ability of a
cell to replicate itself identically
through mitosis.
Lineage – cells that originate
from one stem cell and constitute
a particular tissue type. The
pathway to forming a lineage has
multiple steps.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
Every cell in our body contains more or less the same DNA, yet cells look different
and performs very different functions. This ability to specialize is possible because
not every cell uses its DNA in the same way – cells are different because they use
make different proteins. This lesson will examine how cells regulate which genes are
transcribed into proteins.
Cell differentiation: generating lineages
When a sperm and egg cell fuse to form a single fertilized cell, that one cell holds all the genetic information needed to make a complete person. However, once that one cell has divided to make an entire
person, we find that the cells in our body are not identical, which is why we can’t see with our tongue, or
digest with our feet, or think with our ribs. In order to get from a single cell to a human being two things
must happen: First, the original cell must divide so that there are enough cells to constitute the human
body. Second, at the same time the egg is turning into an embryo and then into a child and then an adult
the cells must specialize to make tongues, feet and ribs for example.
This specialization of cell function is called cell differentiation. In the beginning the undifferentiated egg
divides into a small population of cells that are identical. Each of these cells has the potential to form all
the cells in the body, so they are called stem cells. Because they are made as the fertilized egg is turning
into an embryo they are called embryonic stem cells (ES cells). When an embryonic stem cell divides by
mitosis the siblings it generates are not identical. Instead one sibling looks just like the original ES cell – this
is called self-renewal. The other sibling will enter a cell lineage. A cell lineage is like a family tree that
maps the steps a stem cell takes to turn into a fully specialized cell. There are a number of different cell
lineages – bone cells, muscle cells, nerve cells for example. Most cell lineages require several generations
before a stem cell becomes fully differentiated.
Eventually the body matures and by that time most, but not all cells in a particular lineage will have
completely differentiated. The final stage of differentiation is called terminal differentiation. However
some cells in a lineage will stay immature (these are called progenitor cells). The immature progenitors play an important role if a tissue is damaged: Many terminally differentiated cells, lose the ability to
MC Questions:
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1. Which of the following are properties
of an embryonic stem cell? (Circle all
correct.)
aa. It can self-renew.
bb. It can make blood cells.
cc. It can only make blood cells.
dd. It is only found in the embryo.
65
LESSON READINGS
DEFINITIONS OF TERMS
Terminal differentiation – the
final stage of cell specialization in
which a cell acquires the ability to
perform its mature function.
Progenitor cell – a cell that is
more differentiated than a stem
cell but that still has not terminally
differentiated and may be able
to differentiate into a number of
different cell types.
Adult stem cells – Cells able
to differentiate into different cell
types that are found in mature
tissue.
Express a protein – to make a
protein from DNA.
Wo r k b o o k
Lesson 2.4
divide – neurons and muscle cells are
important examples. But cells must
divide when a tissue needs repair.
Immature progenitors of a cell lineage
that still have the ability to divide are
able to respond to damage when fully
mature members of the lineage cannot.
The adult organism also contains very
immature cells that are more like stem
cells than progenitors because they
can develop into more than one cell
lineage. They are called adult stem
cells, because they are found in adults
not embryos.
MC Questions:
2. Which of the following are behaviors
of progenitor cells? (Circle all
correct.)
aa. Differentiation.
bb. Fertilization.
cc. Loss of the ability to divide.
dd. Self-renewal.
Figure 1: Stem cells can either self-renew
indefinitely or choose to specialize. Specialization
often occurs in multiple steps.
The process of cell differentiation is a
process of ongoing specialization. For
example, just like an elementary school graduate could (in principle) pursue any type of career, so an
ES cell can differentiate into multiple lineages. However as the student begins to specialize their career
options become more limited. A college graduate with a bachelor’s degree in chemistry has chosen a
more limited set of fields that they can work in (like an adult stem cell). If they have a Master’s degree in
physical chemistry those career options are limited even further (like a progenitor cell). Finally a Ph.D. in
molecular spectroscopy is even more specialized (like a terminally differentiated cell).
Regulating cell differentiation: protein expression.
How can some cells retain the ability to divide, while other cells lose that ability? Why are neurons different from blood cells? The differences between cells lie not in their genomic DNA, which is to all intents
and purposes identical between different cells, but in how that DNA is used to make proteins: If a cell not
longer makes Cyclin proteins, it won’t be able to divide; If a cell makes hemoglobin it will be a blood cell.
How a cell behaves depends on the proteins it makes (the term is to express a protein) because proteins
underlie both cell structure and cell function. To briefly review, DNA is divided into genes, each gene
codes for a protein. To express a protein DNA is first transcribed into RNA, then RNA is translated into
protein.
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3. Which of the following cells can
differentiate into the most cell types?
aa. Adult stem cell.
bb. Embryonic stem cell.
cc. Progenitor cell.
dd. Terminally differentiated cell.
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LESSON READINGS
The first step of gene transcription is key and requires two things to happen:
1. The DNA must be available for transcription
2. A transcription factor or factors must bind to the gene’s DNA and permit transcription to occur.
DNA folding determines whether genes are available to be transcribed
DEFINITIONS OF TERMS
If our DNA was loosely wound and all the chromosomes
placed end-to-end, our genomic DNA would be about 2
meters in length! Since an average nucleus is less than
a millionth of a millimeter this clearly doesn’t happen.
Instead DNA in the nucleus is carefully folded around
proteins in the nucleus called histones. Because
histones are positively charged and DNA is negatively
charged the DNA can be packed very tightly. When DNA
is packed tightly like this genes cannot be transcribed
because the RNA polymerase that transcribes the DNA
into RNA cannot get access. Only DNA that is loosely
attached to histones is accessible to RNA polymerase.
Histones – positively charged
proteins that bind DNA and help
to pack DNA in the nucleus.
Acetyl groups – a negatively
charged group with the formula
CH3COO– that when added to
histones neutralizes their positive
charge and prevents them
binding to DNA.
Methyl groups – a positively
charged group with the formula
CH3 that can be added to
histones or DNA. When added to
histones it increases the positive
charge and when added to
DNA it decreases the negative
charge. In both cases this causes
histones and DNA to bind more
tightly to each other.
Epigenetics – the study of how
modifications to the DNA that
do not affect DNA sequence
affect the phenotype of a cell or
organism.
Wo r k b o o k
Lesson 2.4
The first step in ensuring that different types of cells
express the different proteins they need to perform their
specialized functions is to ensure that genes needing to
be expressed have loosely wound DNA, while genes not
needing to be expressed have their DNA packed away
and inaccessible. DNA can be unwound from histones
by adding small chemical groups to histones that are
negatively charged. For example acetyl groups are small
molecules with chemical formula CH3COO–. The negative charge on the acetyl group to decreases the overall
positive charge of histones, and loosens their grip on DNA, allowing RNA polymerase to gain access.
Figure 2: DNA is negatively
charged and histones are positively
charged. When DNA is bound to
histones it will be tightly packed
and inaccessible to RAN polymerase. Modifications that reduce
histone binding open up DNA for
transcription.
Conversely, removing any acetyl groups, or adding chemical groups with positive charges such as
methyl groups with the chemical formula of CH3, will keep histones positively charged giving them a
tighter grip on the negative charges of DNA. DNA can be packed up even more by adding methyl groups
to the DNA itself, reducing its negative charge. The study of how histones and DNA can be modified to
increase or decrease gene expression is called epigenetics, and is currently a growing area in cancer
research.
MC Questions:
4. What is the difference between a
stem cell and an intestinal epithelial
cell? (Circle all correct.)
aa. Only stem cells produce proteins
that regulate cell division.
bb. Only intestinal epithelial cells
produce proteins that regulate
nutrient transport.
cc. Only stem cells can still divide.
dd. Epithelial cells can produce
many different types of cells.
5. Which of the following is a way to
decrease gene expression? (Circle
all correct.)
aa. Adding acetyl groups to
histones.
bb. Adding methyl groups to
histones.
cc. Adding methyl groups to DNA.
dd. Removing methyl groups from
DNA.
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LESSON READINGS
DEFINITIONS OF TERMS
Transcription factors – proteins
that are responsible for promoting
the expression of certain genes.
Transcription factors determine which genes are expressed
MC Questions:
Genes are transcribed by RNA polymerase, which binds to the gene and moves along it, reading the
gene’s DNA sequence and translating it into RNA. But RNA polymerase needs a guide that tells it where
a gene begins and therefore where it should start transcription. Every gene has a small region in front
of the DNA that will code for RNA and eventually protein called the promoter sequence. The promoter
sequence acts as a target for proteins called transcription factors. When a transcription factor is bound
to the promoter sequence, RNA polymerase knows that it should start transcribing that gene into RNA.
Each gene has transcription factors that bind to its promoter sequence. Some of these are specific to a
certain gene, while some transcription factors are shared across gene families.
6. How do transcription factors regulate
gene expression? (Circle all correct.)
aa. By binding specific DNA
sequences.
bb. By copying DNA to make RNA.
cc. By converting RNA to protein.
dd. By indicating to RNA polymerase
that it should bind to a gene.
Cells can use transcription factors to
determine which proteins are expressed.
For instance some transcription factors
present in epithelial stem cells will be
different from terminally differentiated
epithelial cells and the transcription
factors found in terminally differentiated
epithelial cells will be different from those
found in terminally differentiated bone
Figure 3: A gene can only be transcribed when
cells. However, not all gene expression
transcription factors bind to the promoter
sequence at the start of the gene DNA, guiding the
is completely different between different
RNA polymerase into place.
types of cells since all cells have
structures and functions in common –
many components of cell membranes
are identical in different cells for example, and most cells metabolize similarly.
Regulating cell differentiation: cancer.
Wo r k b o o k
Lesson 2.4
Many terminally differentiated cells can no longer divide. This has advantages for tissues like neurons
that are part of an elaborate network. If neurons could continually divide it would be difficult to maintain
such a complex structure like the brain that depends on trillions of precise connections between billions
of neurons. When terminally differentiated neurons that cannot divide are damaged they either die or
cease to function, they do not divide. Hence they have no opportunity to acquire the kind of mutations
that would turn them into hyperproliferating tumors. Because of this there are few if any tumors of mature
neurons. Tumors that appear in the brain are either from the supporting tissues of the stroma or from
primitive progenitor cells that are kept around precisely so they can provide substitutes when neurons are
damaged.
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7. How do transcription factors control
differentiation of the cell?
aa. Changing the expression of
proteins in the cell.
bb. Changing the membrane
potential of the cell.
cc. Changing the folding of DNA.
dd. Changing the lineages of the
cell.
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LESSON READINGS
Not all terminally differentiated cells have lost the ability to divide. Epithelial cells are good examples. As
we learned in lesson 2.1, epithelia are constantly exposed to the environment and therefore extremely
vulnerable to damage so epithelial tissue needs to be constantly prepared to repair damage. Because of
this they have ample opportunity to acquire tumor-causing mutations, and indeed, as we have seen, the
majority of cancers arise from epithelial cells.
DEFINITIONS OF TERMS
Tumorigenic – an event that
causes a tumor to form.
Many tissue types, especially those whose terminally
differentiated cells have lost the ability to divide, keep a
store of progenitors that they use to replace terminally
differentiated cells if they are damaged. These progenitors are less vulnerable to acquiring mutations than we
might imagine because they don’t divide continuously,
only when they receive a signal to do so. In this regard
however, one of those signals comes from inflammation, so people suffering from continual low levels of
inflammation are vulnerable. Another reason some
tissues maintain a store of progenitors is to replace
cells that have a short life span – blood and immune
cells are examples of this. These cells are continuously
dividing and so they are vulnerable to acquiring tumorigenic mutations, and indeed cancers of the blood are
common.
8. Which kinds of cells are least
vulnerable to tumorigenic
mutations?
aa. Stem cella;
bb. Epithelial cells;
cc. Neurons; or
dd. White blood cells.
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Figure 4: Germ cells are cells
in our body that can differentiate
into any cell type. This is why some
germ cell tumors form teeth!
Finally the most primitive cells in the body are the germ cells (eggs and sperm) because they fuse to form
an embryonic stem cell that can make all body components. Tumors of germ cells are quite common and
interestingly often contain many different tissue types. Fortunately most germ cell tumors are benign.
Wo r k b o o k
Lesson 2.4
MC Questions:
9. True or False: tumors are common in
all types of cells
aa. True
bb. False
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STUDENT RESPONSES
What is the purpose of differentiation, and why do cancer cells typically not form from highly differentiated cells?
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Wo r k b o o k
Lesson 2.4
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70
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
DEFINITION
Acetyl groups
The molecule CH3COO– that can be added to histones to put DNA in an “open” form and promote gene
expression.
Adult stem cells
Unspecialized cells that form a number of different (but not all) cell types in the body.
Dedifferentiation
The process where cell specialization is lost in favor of general cell behavior, like growth.
Differentiation
The process of cellular specialization.
Epigenetics
The study of how modifications to the DNA that do not affect DNA sequence affect the phenotype of a cell
or organism.
Germ cell
A cell that gives rise to sperm or egg cells which has high potency.
Histones
Positively charged proteins that bind DNA and help to pack DNA in the nucleus.
Lineage
The group of cells that are related that originated from one specialized cell in human development.
Methyl groups
The molecule CH3 that can be added to histones or DNA to pack DNA more tightly and inhibit gene
expression.
Embryonic stem (ES)
cells
Cells from an early stage in human development that can form any type of cell in the body.
Potency
The ability of a cell to differentiate into various cell types.
Progenitor cell
A cell that is more differentiated than a stem cell but still able to differentiate into a number of different cell
types, but cannot undergo self-renewal.
Self-renewal
The ability of a cell to replicate itself identically through mitosis.
Terminally differentiated
cell
A cell that is differentiated to the highest level, so that it performs a specific function in the cell, and is not
able to replicate.
Transcription factors
Proteins that are responsible for promoting the expression of certain genes.
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LESSON 2.5 WORKBOOK
How do cells die?
DEFINITIONS OF TERMS
Anti-oxidants – a molecule that
inhibits the activity of reactive
oxygen species preventing them
damaging DNA.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.5
Cells can have three fates: They can divide, they can differentiate or they can die.
But while cell death following trauma is a passive process cells also have a built-in
program to actively destroy themselves, called apoptosis. In a normal cell, prosurvival signals prevent cells destroying themselves, but when a cell ages or when
its DNA becomes too damaged to repair, the cell can no longer respond to prosurvival signals are and the apoptosis program is switched on. This lesson investigates what happens during apoptosis and how cancer cells can cheat death.
Cell responses to damage: apoptosis
With the exception of stem cells that can replicate indefinitely, cells, like people have finite lifespans. For
most cells lifespan is dictated by the amount of DNA damage they accumulate. Each time a cell divides
its DNA, errors in replication cause the DNA to mutate randomly. External events can also damage
DNA in addition to the normal errors in replication it accumulates at each cell division. Normally the cell
will stop cell cycle progression temporarily so that DNA repair proteins can fix any DNA damage. DNA
repair enzymes are not 100% successful however, and some mutations will escape, eventually leading to
functional defects that are the equivalent of cellular aging. As cells age they will acquire so many mutations
that they can no longer function normally at all. Then the cell will die.
What kind of external events damage DNA? Cellular DNA is particularly vulnerable to the byproducts of the
normal respiration processes cells need to survive: When oxygen is broken down in the cell it produces
reactive oxygen species (ROS), compounds that react with DNA causing mutations or breaks in DNA.
Any compound that behaves like ROS in this way are called mutagens. Some, but not all carcinogens are
mutagens. Another significant mutagen that originates outside the cell is the UV radiation in sunlight. UV
radiation is obviously particularly dangerous for skin cells. The DNA damage that mutagens like ROS and
UV radiation cause is one of the major causes of cellular aging. As a result many so-called anti-aging products feature anti-oxidants, compounds that eliminate the ROS produced by oxidation reactions, thereby
hopefully delaying the aging process. Similarly certain foods (like blueberries) that are high in anti-oxidants
are recommended because they can scavenge the ROS produced as a result of cellular metabolism,
thereby staving off cellular aging.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Apoptosis – the process of programmed cell death in multicellular organisms characterized by
cell shrinkage, nuclear fragmentation, degradation of proteins,
and release of cellular “blebs”.
This is an organized and planned
death of a cell.
Necrosis – the premature death
of a normal cell in which it bursts,
randomly releasing fragments of
proteins and DNA into surrounding tissue. This unplanned death
is disorganized.
Phagocytic cells – cells that are
responsible for consuming foreign
particles, bacteria, and cellular
blebs. These cells break down
contents of what they consume
and recycle them for other cells
to use.
Wo r k b o o k
Lesson 2.5
The more mutations cellular DNA
accumulates, whether due to errors
of replication or damage by ROS
or other mutagens the more likely
they are to prevent the cell from
functioning normally, and the more
unlikely DNA repair mechanisms
will be able to fix them during the
cell cycle. At that point the cell will
activate a program to kill itself called
apoptosis.
Figure 1: An apoptotic cell (a) and a necrotic cell
(b) show exhibit two types of cell death. Apoptosis is
a regulated dismantling of the cell, while necrosis is an
unregulated explosion of cellular contents.
During apoptosis, the cell shrinks
itself down in size, and produces enzymes that break down all the contents of the cell, including cellular
proteins and DNA. The cell debris this breakdown causes is then released from the dying cell in little
packets known as cellular ‘blebs’. The cellular blebs end up outside the cells where cells of the immune
system called phagocytes (from the Greek meaning ‘cell eater’) consume them by phagocytosis.
Macrophages are an example of such immune system phagocytes. Once macrohpage has phagocytosed a bleb containing protein and DNA debris from an apoptosing cell it recycles the contents of the
bleb for its own use. Apoptosis is therefore like cellular suicide: a cell takes its own life because it is no
longer functional. As it dies it is cannibalized by its neighbors to the ultimate benefit of the community as
a whole. While we are young the gap left by the cell that has apoptosed is rapidly filled by a new cell that
has just been produced, but as we get older we come less efficient at replacing damaged cells and tissue.
In this way cellular aging translates into bodily aging.
The scenario in which ROS damage DNA and activate apoptosis is known as intrinsic apoptosis. This
means that the signal to start producing the enzymes that digest the damaged cell’s DNA and proteins
comes from inside the cell itself – in this case the intrinsic signal is provided by DNA damage.
A second type of apoptosis is known as extrinsic apoptosis. In this case the signal to start producing
the apoptosis enzymes comes from outside the cell. Examples of signals like this are lack of oxygen and
tissue damage. A good example of an extrinsic signal occurs when a cell is infected with a virus and
activates the immune pathway that ends up with killer T cells. The killer T cells then send a signal to the
infected cell telling it to initiate apoptosis.
MC Questions:
1. When is apoptosis activated? (Circle
all correct.)
aa. A cell has accumulated too
much DNA damage.
bb. A cell cannot enter the cell cycle.
cc. A cell has grown too large.
dd. A cell has received signals to
die.
2. Which of the following is a difference
between apoptosis and necrosis?
(Circle all correct.)
aa. Apoptosis is only activated from
external signals necrosis is not.
bb. Necrosis activates immune
response, apoptosis does not.
cc. Apoptosis causes the cell to
break down, necrosis does not.
dd. Apoptosis is organized, necrosis
is not.
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LESSON READINGS
Not all cell death occurs through apoptosis. When a normal cell is physically damaged by trauma it can
suddenly burst and release its contents explosively to the environment. This is known as necrosis. In this
case also release of the cell contents recruits immune phagocytes to the area and they consume the cell
debris.
The best way to describe the difference between apoptosis and necrosis is that apoptosis dismantles the
cell in an organized fashion whereas necrosis is an unorganized cellular explosion.
Apoptosis: a struggle between life and death
DEFINITIONS OF TERMS
The severe DNA damage that triggers apoptosis is detected by a specific protein called p53. The protein
p53 plays a critical role in controlling DNA damage within normal cells:
■■ When DNA damage has occurred p53 is the protein that stops the cell cycle progressing.
■■ When DNA damage is fixable p53 is the protein that activates transcription of the DNA repair
enzymes that can repair the DNA.
Caspases – a family of proteins
involved in apoptosis that are
responsible for breaking down
proteins and DNA in the cell.
Wo r k b o o k
Lesson 2.5
MC Questions:
3. Which of the following is a direct
activity of p53? (Circle all correct.)
aa. Control entrance of cell into cell
cycle.
bb. Repair DNA damage.
cc. Activate apoptosis.
dd. Break down proteins for
apoptosis.
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However if DNA damage is irreparable, p53 is the protein that activates apoptosis. How?
Cellular proteins and DNA are broken down during apoptosis because the dying cells start to express a
series of enzymes: proteases called caspases that break down proteins) and DNAases (that break down
DNA) that normal cells don’t produce.
Signaling the cell to produce these
enzymes is a critical first step in switching
on the apoptosis program and p53 can
control expression of these enzymes both
directly and indirectly:
■■ p53 controls expression of apoptosis enzymes directly by activating
expression of transcription factors
that bind to the protease and DNAase
genes. When the transcription factor
proteins are expressed and bind to
the genes this permits the enzyme
genes to be transcribed (we learned
how transcription factors work in the
last lesson.
Figure 2: The process by which apoptosis is
triggered by p53 activation which leads to degradation of proteins and DNA by caspases, forming
'blebs' that are consumed by other cells.
4. Which proteins are directly
responsible for degrading the
contents of the cell for apoptosis?
(Circle all correct.)
aa. p53
bb. Rb
cc. DNA repair proteins
dd. Caspases
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LESSON READINGS
■■ p53 can activate apoptosis indirectly by damaging mitochondria. Mitochondria are the organelles chiefly responsible for generating energy in cells. To generate energy they need an intact
membrane. P53 can send signals to the mitochondria that cause their membranes to become leaky.
Apoptosis occurs in cells with leaky mitochondria.
p53 is called a pro-apoptosis factor, but it is not the only one. Both the intrinsic and extrinsic apoptosis
pathways also activate other pro-apoptotic factors that can poke holes in mitochondria and make them
leak (these include the proteins Bax and Bak, as seen in Figure 3).
DEFINITIONS OF TERMS
MC Questions:
5. During which step of apoptosis is
there a competition between proapoptotic factors and pro-survival
factors? (Circle all correct.)
aa. Extrinsic signaling pathway.
bb. DNA damage.
cc. Making holes in mitochondria.
dd. Degrading cellular proteins.
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Pro-apoptotis factors – proteins
that promote apoptosis by making mitochondrial membranes
leaky.
Pro-survival factors – proteins
that inhibit apoptosis by preventing mitochondria leaking, thereby
promoting cell survival.
Figure 3: Pro-apoptotic factors like Bax or Bak make holes
in the mitochondria to release contents. Release of contents
activates caspases which leads to apoptosis. Alternatively, prosurvival factors, like Bcl-2, inhibit formation of mitochondrial
pores and prevent apoptosis.
Apoptosis happens when a cell’s DNA is too damaged to repair, but the mechanisms that lead to
apoptosis are very sensitive and are already primed and ready to go in cells with normal amounts of DNA
damage. They are prevented in these normal cells because surrounding tissues secrete survival signals
to keep apoptosis under control so that it is only activated when necessary. These signals are called
pro-survival factors (an example is Bcl-2 in Figure 3). Bcl-2 can promote cell survival by activating
mechanisms that repair the holes in mitochondria to prevent them leaking.
Wo r k b o o k
Lesson 2.5
Bcl-2 is a pro-survival signals because it opposes the indirect effects of p53. Other pro-survival signals
can also turn down the volume on p53 so it behaves appropriately. Because p53 controls DNA damage
in both normal and dysfunctional cells it is important that it doesn’t overreact to normal damage by starting
apoptosis in normal cells.
6. Which is the most common way that
cancer cells subvert the activation of
apoptosis? (Circle all correct.)
aa. Inactivating pro-survival
proteins.
bb. Inactivating pro-apoptosis
proteins.
cc. Hyperactivating pro-survival
proteins.
dd. Hyperactivating pro-apoptosis
proteins.
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LESSON READINGS
DEFINITIONS OF TERMS
NF-кB – a transcription factor
that promotes expression of prosurvival proteins. This protein is
often overactive in cancer cells.
Tumor suppressor protein – a
protein that controls cell proliferation so that cells don’t proliferate abnormally. This includes
proteins that prevent growth and
survival.
How cancer cells cheat death
MC Questions:
Because apoptosis destroys cells with serious mutations that affect their functions it is a critical mechanism for preventing tumor formation. As we will see in later units, both the intrinsic apoptosis pathway (via
p53) and the extrinsic apoptosis pathways (via immune cells) are pretty efficient at killing off cells that have
accumulated tumorigenic DNA damage. However, some of these cells can go on to accumulate further
mutations that either inhibit pro-apoptotic pathways, or hyperactivate pro-survival pathways. In either case
a cell that is resistant to apoptosis control will result.
7. What is the direct activity of NF-кB?
(Circle all correct.)
aa. Bind pro-survival receptors.
bb. Activate expression of prosurvival genes.
cc. Mutate pro-apoptotic proteins.
dd. Prevent leakage of mitochondrial
contents.
Tumor cells most commonly resist apoptosis is by inhibiting pro-apoptotic proteins like p53. As a result
upwards of 60-80% of cancers have mutations that inactivate p53. This shows just how important p53 is
for controlling DNA damage in cells.
When tumor cells are investigated to see what mutations they have, mutations that disrupt the apoptosis
pathways often coincide with mutations that activate survival pathways. The transcription factor, NF-кB
(pronounced NF-kappa B) activates one of the most powerful pro-survival pathways. NF-кB binds to
genes that prevent apoptosis being initiated. So when the NF-кB pathway is overactive, as it is in many
tumors, apoptosis can’t be switched on. So there are two ways that tumor cells interfere with apoptosis:
1. They can switch off pathways that switch apoptosis on.
2. They can switch on pathways that switch apoptosis off.
In both cases the cancer cell cheats death.
Apoptosis is only one of many mechanisms that cells used to control their growth. Proteins that control cell
growth are called tumor suppressors and we have learned about several in this unit:
■■ The retinoblastoma protein (Rb) makes sure the cell passes through the cell cycle ‘gate’ with intact
DNA
■■ The cell cycle checkpoint proteins (INK proteins) make sure the hand-off between the different
stages of the cell cycle doesn’t occur until the cell is ready.
■■ The pro-apoptosis proteins (p53, Bax/Bak) make sure that cells that are too damaged cells die.
Wo r k b o o k
Lesson 2.5
These regulators of the community of cells promote the ‘laws’ that keep the tissue community intact. Now
that we know what the normal laws are, the next unit will help us understand how cancer cells violate
them.
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76
STUDENT RESPONSES
Describe 2-3 ways that cancer cells can disrupt apoptosis. Hint: Think of the steps necessary for apoptosis to occur from the
initial apoptosis stimuli (either activation of apoptotic signaling or DNA damage) to cell blebbing.
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Wo r k b o o k
Lesson 2.5
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77
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.5
DEFINITION
Anti-oxidants
A molecule that inhibits the activity of reactive oxygen species preventing them damaging DNA.
Apoptosis
The process of programmed cell death in multicellular organisms characterized by cell shrinkage, nuclear
fragmentation, degradation of proteins, and release of cellular 'blebs'. This is an organized and planned
death of a cell.
Caspases
A family of proteins involved in apoptosis that are responsible for breaking down proteins and DNA in the
cell.
Necrosis
The premature death of a normal cell in which it bursts, randomly releasing fragments of proteins and DNA
into surrounding tissue. This unplanned death is disorganized.
NF-кB
A transcription factor that promotes expression of pro-survival proteins. This protein is often overactive in
cancer cells.
Phagocytic cells
Cells that are responsible for consuming foreign particles, bacteria, and cellular blebs. These cells break
down contents of what they consume and recycle them for other cells to use.
Reactive oxygen species
(ROS)
Chemically reactive molecules of oxygen that can mutate or break DNA to cause damage.
Pro-apoptotic factors
Proteins that promote apoptosis by making mitochondrial membranes leaky.
Pro-survival factors
Proteins that inhibit apoptosis by preventing mitochondria leaking, thereby promoting cell survival.
Tumor suppressor
protein
A protein that controls cell proliferation so that cells don’t proliferate abnormally. This includes proteins that
prevent growth and survival.
78
Unit 3:
Unit 3: Introduction
Where are we heading?
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a 'normal' cell?
Unit 3: How do normal cells become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How is cancer diagnosed and treated?
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In Unit 3 we'll zoom in on how cell function is
disrupted in cancer.
Lesson 3.1 will give you the opportunity to apply your understanding
about DNA replication and protein synthesis to an investigation of
how DNA is organized, and how mutations can affect gene function.
Lesson 3.2 examines how DNA mutations affect protein synthesis and
how this may promote development of cancer. Lesson 3.3 investigates the internal clock that allows a cell to age normally, and how
this clock is disrupted in cancer. Lesson 3.4 explores how cancer
cells become immortal by cheating normal cell death. Lesson 3.5
grapples with the idea that each cancer cell evolves independently,
so that each tumor has different characteristics.
79
LESSON 3.1 WORKBOOK
What is in our DNA sequence?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
Gene expression – the process
by which information from
a gene-coding region of DNA is
used to make a protein.
Somatic cells – All cells that
aren’t eggs or sperm
Autosome – one of 22 chromosomes in human DNA that is
found in females and males
Zygote – Fertilized egg
Wo r k b o o k
Lesson 3.1
The previous Unit described the regulatory mechanisms that keep normal cells
normal. We learned that these mechanisms occur through the activity of proteins,
which are encoded in our genomic DNA. Tumors and cancer occur when DNA is
mutated so that those regulatory proteins can no longer control cellular behavior.
This lesson explains how genomic DNA is organized, and how that organization
can dynamically regulate gene expression to impact cell behavior.
What is in our DNA sequence?
We have learned in other modules, as well as in Unit 2, how the activity of the proteins a cell synthesizes
determines that cell’s behavior. So to understand cell behavior we need to understand those proteins and
how they work. Each protein is encoded by a DNA sequence called a gene. The gene’s DNA sequence is
first transcribed into an RNA sequence, and then the RNA sequence is then translated into an amino acid
sequence that forms a protein. As the protein matures it folds into a characteristic 3-dimensional shape that
permits it to perform its function. For example receptor proteins always contain a binding ‘pocket’ where
their specific ligand can fit. Generating proteins from gene sequences is also known as gene expression
and altering gene expression, for instance following DNA mutation, can have serious effects on cell behavior. For example, as we learned in Unit 1, proto-oncogenes are genes that normally make sure that cell
proliferation is tailored to tissue requirements. However, when proto-oncogenes mutate to form oncogenes,
proliferation is no longer regulated and tumors form. Understanding how DNA is organized will give us a
better idea of how and when the important functional mutations to genes occur.
Most somatic cells have 23 pairs of chromosomes. 22 pairs of chromosomes are found in both male and
female cells, these chromosomes are called autosomes, while the 23rd pair, called sex chromosomes,
can take one of two forms. Female cells usually have the XY form, whereas males usually have YY. Germ
cells (eggs and sperm) only have one of each chromosome rather than a pair, because they fuse together
during fertilization to produce the zygote which then has 23 pairs of chromosomes.
MC Questions:
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1. True or false: Gene expression refers
to generating proteins from DNA.
aa. True.
bb. False.
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2. Which of the following does the
genome contain?
aa. Autosomes;
bb. Introns;
cc. Exons;
dd. All the above.
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LESSON READINGS
DEFINITIONS OF TERMS
Genome – The complete sequence
of all the chromosomes
Exons – the nucleotide sequence
of a gene that codes for protein
sequence.
Introns – Parts of a gene between
exons that do not contain sequence
necessary for protein coding, and
are removed prior to translation.
Non-coding DNA – DNA sequences that do not make protein. They
may make RNA molecules that are
necessary for gene expression.
Transposon – a segment of DNA
that is capable of moving into
another position in a genome.
Retrotransposon – a segment of
DNA that is capable of copying itself
into RNA and undergoing reverse
transcription to form a new DNA
segment that can move into another
position in the genome.
Wo r k b o o k
Lesson 3.1
Human chromosomes contain 32 billion
nucleotides. All of these nucleotides together
make the human genome. Figure 1 shows
how the genome is divided into various types
of functions. When the human genome was
first fully sequenced in 2001, it was clear that
only a very small proportion, maybe 2%,
contains DNA that actually codes for genes.
People found this very surprising because at
the time it was not at all obvious what the rest
of the genome was for. For a long time the
remaining 98% was dismissed as ‘junk’ DNA
Figure 1: Genes compose only 2% of all the
that we had somehow acquired during evoluDNA sequence in our genome. The majority
tion, but that had no functional significance. In
of sequence is composed of retrotransposons,
DNA transposons, and noncoding DNA.
fact, the non-protein encoding DNA sequence
turns out not to be ‘junk’ at all; instead it is
composed of important sequences that can
regulate how and when gene expression occurs. The DNA sequences that directly code for amino acids
are called exons (called genes in Figure 1). Interspersed within exons are sequences called introns.
Introns are non-coding DNA that play important roles in regulating how exons are expressed. Yet
other non-coding DNA sequences (the green wedge in Figure 1) can be transcribed into RNA but are
not translated into protein. Some of these RNA sequences, like transfer RNA (tRNA) or microRNAs help
protein translation. Another large component are regulatory sequences that also affect gene expression
without making RNA. Finally a major chunk of non-coding DNA sequences are called DNA transposons
and retrotransposons. These sequences can actually jump around the genome from one location to
another. Obviously, if they land in a gene sequence they can affect gene expression. Thus even though
most of the genome does not code for protein directly it does play an indirect role in regulating protein
expression.
Genome organization: gene sequences.
As we learned in Lesson 2.4, DNA is packaged around histones, with the tightness of the packaging
determining whether or not DNA will be transcribed. We learned in Lesson 2.5 DNA can be transcribed
when it is loosely packed and that it is transcribed when a transcription factor binds to a promoter
sequence (also known as a regulatory sequence) a stretch of non-coding DNA located just in front of
the coding sequence. When the transcription factor is bound to the regulatory sequence, RNA polymerase can bind to the coding sequence of the DNA and transcribe the gene into RNA. Up to now we
only learned about transcription factors that promote gene expression, but inhibitory transcription factors
MC Questions:
3. Which of the following DNA
sequences are most prevalent in the
genome?
aa. Genes;
bb. Introns;
cc. Non-coding DNA;
dd. Retrotransposons.
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4. True or false: Most of our DNA
contains sequence involved in
protein expression.
aa. True.
bb. False.
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LESSON READINGS
also exist. When they bind to the regulatory sequence, they block it and prevent gene expression. Regulatory sequences therefore play multiple roles to stimulate and inhibit gene expression some of which are
extremely complex
DEFINITIONS OF TERMS
Transcription factor – Protein
that binds to a DNA sequence
at the start of a gene and either
promotes or inhibits transcription.
Each gene is composed of two regions – the region that codes for the amino acids in the protein, called
the exon, and non-coding regions interspersed among the exons called introns. As a result the DNA
sequence of a gene in the genome is often considerably longer than the sequence of the protein that will
result at the end of translation (remember that each amino acid is coded for by three nucleotides). The
progression from DNA to RNA to protein is illustrated graphically in Figure 2, which represents the gene
sequence for a protein with 10 exons, each colored differently. We can see how, in the DNA sequence,
each exon is separated from another by a log stretch of non-coding introns (represented by the dotted
line). Both the exons (colored) and the introns (black line) are transcribed into RNA, but when the RNA is
translated into protein the introns are removed, so that the protein is now a single molecule composed of
the different introns. The process of removing the introns from RNA as it is translated into protein is called
splicing. As a result the size of the protein is much smaller than the size of the RNA and much, much
smaller than the size of the gene.
Regulatory sequence – a segment of DNA that is responsible
for increasing or decreasing the
expression of specific genes in
the cell.
Figure 2: Genes are composed of short coding sequences called
exons, which are separated by longer, non-coding sequences called
introns. When a gene is transcribed into RNA, both introns and
exons are included in the sequence. Introns are removed from
mRNA sequence, leaving only exon sequence to make proteins.
Wo r k b o o k
Lesson 3.1
What is the purpose of introns and exons? Dividing the protein up into chunks like this provides an
opportunity to create protein diversity. Sometimes when an intron is removed an exon will be removed
along with it. For example a protein without the yellow exon could potentially be very different from the
protein with it, if the yellow exon provided the protein with an important function – for example the ability to
respond to signals from the environment.
MC Questions:
5. What is the best description of
regulatory sequence?
aa. DNA sequence encoding
proteins that regulate cell
behavior;
bb. DNA sequence that regulates
gene expression;
cc. DNA sequence that regulates
cell cycle;
dd. DNA sequence that regulates
translation.
6. Which of the following best
describes the purpose of splicing?
aa. Removal of intron DNA
sequence to allow for translation
of exon sequence;
bb. Removal of intron RNA
sequence to allow for translation
of exon sequence;
cc. Removal of exon DNA sequence
to allow for translation of intron
sequence;
dd. Removal of exon RNA sequence
to allow for translation of intron
sequence.
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LESSON READINGS
Introns perform two important functions in a gene: First, having large stretches of intron DNA can act as
a kind of ‘insulation’ for the coding sequences in the exon. If most of the DNA in a gene is not involved in
coding for protein, random mutations to the gene are less likely to affect an important region, even if the
gene is unfolded ready for transcription and therefore vulnerable to carcinogens. Second it has recently
been discovered that introns actually contain regulatory sequences that can control how much RNA is
transcribed from the gene, therefore regulating protein levels. This can be
Non-gene sequences in the genome
DEFINITIONS OF TERMS
Transposable element – the
collective term for transposons
and retrotransposons, or any
DNA sequence that can change
its position within a genome.
Reverse transcriptase – the
enzyme responsible for copying
an RNA template into a doublestranded DNA sequence. This
is used in retroviruses and in
retrotransposons.
Wo r k b o o k
Lesson 3.1
Maybe surprisingly, over half of the genome sequence is not fixed in place. Instead it is composed of
moveable segments of DNA collectively called transposable elements. These moveable elements are
divided into two groups DNA transposons and retrotransposons that move around differently. DNA transposons can actually cut themselves out of the genomic DNA and paste themselves into another region
– not surprisingly this is called ‘cut and paste’ because the DNA sequence is no longer in its usual place.
On the other hand retrotransposons are transcribed into RNA and then re-converted back into DNA
by an enzyme called reverse transcriptase. You may remember from the ID module that reverse
transcriptase is essential to the
replication cycle of HIV. Reverse
transcriptase, which is encoded
within the retrotransposon
sequence itself is able to convert
single-strand RNA sequences into
double-stranded DNA sequences,
which can then insert themselves
somewhere else in the DNA. In
the case of retrotransposons there
are therefore now 2 copies in
the genome – one in the original
location and the second somewhere
else in the genome.
Genomic DNA is clearly a dynamic
flexible molecule rather than an
inert sequence. The moveable
sequences of DNA allows for
diversity. Having DNA that can
move around can disrupt gene
Figure 3: Transposon movement occurs through
a “cut and paste” manner, where the transposon is
removed from the original DNA sequence and inserts
into a new location. Retrotransposons move through
a “copy and paste” method, where the RNA copy of
the retrotransposon is converted into DNA, which
then inserts into another site of DNA.
MC Questions:
7. Which of the following is a useful
function of introns? (Circle all
correct)
aa. Promoting cell survival.
bb. Providing diversity of gene
expression.
cc. Regulating gene expression.
dd. Spacing of exon sequence.
8. True or false: Transposable elements
do not express proteins.
aa. True.
bb. False.
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LESSON READINGS
expression when they insert inappropriately into genes. Having reverse transcriptase could lead to
duplication of actual genes if the reverse transcriptase transcribed and then inserted them somewhere
else. This could clearly be a problem if that gene is a proto-oncogene, and in fact there are several
examples of proto-oncogenes to which this has happened.
DEFINITIONS OF TERMS
Epigenetic silencing – the
silencing of expression of certain
regions of DNA through modification of its DNA sequence.
Wo r k b o o k
Lesson 3.1
Fortunately, most transposable elements are tightly wrapped around histones, which inhibits their function
in the same way that tight wrapping prevents gene expression. In the case of transposable elements,
this is called epigenetic silencing. However, as we learned in Unit 2 if tumor formation disrupts the
packaging of DNA it can also stop the epigenetic silencing of genes involved in transposon/retrotransposon movement. As a result the activity of transposons and retrotransposons is increased significantly in
cancer, which, as we will see in the next lesson, increases the chance that genes important for keeping
cells normal will become mutated.
MC Questions:
9. How do transposable elements
affect gene expression? (Circle all
correct.)
aa. Disrupt a gene sequence by
insertion.
bb. Induce epigenetic silencing of
genes.
cc. Reverse transcription of gene
RNA sequences.
dd. Decrease length of introns.
10.Which of the following
explains why there are
more retrotransposons than
transposons in our genome?
aa. Retrotransposons use a “copy
and paste” strategy to move.
bb. Retrotransposons use a “cut
and paste” strategy to move.
cc. Retrotransposons are
normally highly active in the
cell.
dd. Transposons are more
inactive in the cell than
retrotransposons.
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STUDENT RESPONSES
Describe 2-3 reasons why the 98% of our DNA that does not encode proteins should not be called 'junk' DNA. _____________________________________________________________________________________________________
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Wo r k b o o k
Lesson 3.1
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85
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.1
DEFINITION
Autosome
One of 22 chromosomes in human DNA that is found in females and males
Complementary A sequence of DNA or RNA that contains the appropriate sequence of nucleotides to pair with another
strand of DNA or RNA.
Diploid
Any cell that has a pair of chromosomes, or two sets of chromosomal DNA.
Epigenetic silencing
The silencing of expression of certain regions of DNA through modification of its DNA sequence.
Exons
The nucleotide sequence of a gene that codes for protein sequence.
Gene expression
The process by which information from a gene coding region of DNA is used to make a protein.
Genome
The complete sequence of all the chromosomes
Haploid
Any cell that only has a single set chromosomal DNA.
Introns
Parts of a gene between exons that do not contain sequence necessary for protein coding, and are
removed prior to translation.
Meiosis
The process of cell division in sexually reproducing organisms that reduces the number of chromosomes
from diploid to haploid.
Non-coding DNA
DNA sequences that do not make protein. They may make RNA molecules that are necessary for gene
expression.
Regulatory sequence
A segment of DNA that is responsible for increasing or decreasing the expression of specific genes in the
cell.
Retrotransposon
A segment of DNA that is capable of copying itself into RNA and undergoing reverse transcription to form a
new DNA segment that can move into another position in the genome.
Reverse transcriptase
The enzyme responsible for copying an RNA template into a double-stranded DNA sequence. This is used
in retroviruses and in retrotransposons.
Somatic cells
All cells that aren’t eggs or sperm
Transcription factor
Protein that binds to a DNA sequence at the start of a gene and either promotes or inhibits transcription.
86
TERMS
TERM
DEFINITION
Transposable element
The collective term for transposons and retrotransposons, or any DNA sequence that can change its position within a genome.
Transposon
A segment of DNA that is capable of moving into another position in a genome.
Zygote
Fertilized egg
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.1
87
LESSON 3.2 WORKBOOK
How do normal cells become
cancer cells?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
The key factor that determines whether a normal cell will become a tumor is the
kind of mutations it acquires. Most mutations do not affect cell function, and those
that do usually lead to cell death. However, a minority of mutations can both affect
cell function and allow the cell to live. Of those mutations, only a minority leads
to cancer. In this lesson, we will explore how cells acquire random mutations and
how carcinogens increase the chance that very rare cancer-causing mutations will
accumulate.
DNA mutations and tumor formation
In Unit 2, we learned how critical it is for cells in tissues to work together as a community, and for tissue
communities to work together to regulate organ function. Tumor formation occurs when cells lose their
ability to participate as members of a tissue community, and this may eventually disrupt organ function too.
The key change in cellular behavior that precipitates this loss of function occurs when cells accumulate
mutations in their DNA that modify critical proteins. This change in a normal cell’s DNA so that the cell
forms a tumor is called transformation.
Transformation – the process
by which a cell acquires characteristics of a tumor cell.
DNA acquires random mutations for a variety of reasons, but the most common include:
■■ DNA polymerase errors — the DNA polymerase enzyme duplicates DNA during S phase as the
cell prepares for mitosis. DNA polymerase makes a mistake once in every 10 million bases it copies.
■■ Mistakes during mitosis — for mitosis to occur cleanly chromosomes must be divided equally
between the daughter cells. This does not always occur.
Wo r k b o o k
Lesson 3.2
■■ Effects of environmental agents — environmental agents called mutagens can modify the chemical structure of the DNA bases themselves, or promote errors DNA polymerase and/or mitosis. Most
mutagens are also carcinogens, but not every carcinogen is a mutagen.
MC Questions:
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1. Transformation describes which of
the following types of cell?
aa. A cell that has acquired
mutations
bb. A cell acquiring spreading traits
cc. A cell that can replicate
indefinitely
dd. A cell entering the blood stream
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LESSON READINGS
DEFINITIONS OF TERMS
Mutagen – any chemical or
agent that is capable of mutating
DNA sequence.
Somatic cell – any cell that
forms the body of an organism
that is not a germ cell.
Germline mutation – any
detectable mutation or variation
of DNA present within germ cells
that is inherited by offspring of
that individual.
BRCA1– a tumor suppressor
gene involved in DNA repair,
whose mutated form is associated with breast and ovarian
cancer as well as other cancers.
BRCA2 – another tumor suppressor gene involved in DNA
repair, whose mutated form is associated with breast and ovarian
cancer as well as other cancers.
Wo r k b o o k
Lesson 3.2
As we know, there are two types of cell in the body: Germ cells (eggs and sperm) and somatic cells.
Germ cells contain one copy of the genome on 23 chromosomes, while somatic cells contain two copies
of the genome on 23 pairs of
chromosomes. When germ
cells fuse they form a zygote
with two copies the genome
on 23 pairs of chromosomes.
Whatever mutations the
germ cells have acquired will
therefore be inherited by the
zygote, so that each somatic
cell in the offspring will also
Figure 1: Pictures of normal epithelial cells of the mammary
have the mutation. Inheritable
duct (left) compared to transformed epithelial cells of the
mutations like this are called
mammary duct (right). Normal cells are generally more strucgermline mutations. If the
tured and ordered within the tissue compared to transformed
cells.
germline mutations have the
potential to cause the cell to
transform into a tumor they can genetically predispose individuals that have them to develop cancer.
One example of a germline mutation that plays a critical role in predisposition to a number of different
cancers occurs to the tumor suppressor protein BRCA1 that is involved in DNA repair Mutated forms
of BRCA1, which stands for ‘BReast CAncer susceptibility protein’, have been conclusively linked to
predisposition to developing breast cancer. When mutations to BRCA1 are seen together with mutations
to another tumor suppressor protein, BRCA2 the likelihood of developing breast cancer by the age of 70
increases to 50-65% while the likelihood of developing ovarian cancer increased to 35-46%. Mutations
to BRCA2 alone increase the likelihood of developing breast cancer to 40-57% and ovarian cancer to
13-23%. Mutations in BRCA1/2 are also risk factors for colon, prostate, and pancreatic cancer.
Unlike germline mutations that are found in eggs and sperm and therefore inherited by every zygote
produced when the germ cells fuse, somatic mutations are found in somatic, not germ cells. As a result
they will only affect the individual who acquired the mutation, but will not be inherited by their offspring.
Somatic mutations also only affect the cell that acquired that mutation, and no other cell in the body.
Somatic mutations that lead to tumor formation and hence cancer are therefore found only in those tumor/
cancer cells and not throughout the body.
MC Questions:
2. Which of the following can lead
to cell transformation? (Circle all
correct.)
aa. DNA polymerase errors.
bb. Mistakes of mitosis.
cc. Exposure to mutagens.
dd. Exposure to carcinogens.
3. Which of the following is true of
BRCA1? (Circle all correct.)
aa. It is a tumor suppressor gene.
bb. It is mostly active in breast and
ovarian cancers.
cc. Mutations in the gene cannot be
passed to offspring.
dd. Mutations in the gene increase
cancer risk.
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LESSON READINGS
Types of DNA mutations
DEFINITIONS OF TERMS
Somatic mutation – a change
in DNA sequence of a cell that is
not inherited by the offspring.
Neutral mutations – mutations
that do not affect the ability of a
cell to function or survive. These
include any mutation in a noncoding sequence, or synonymous
DNA mutations that do not affect
protein sequence.
Synonymous mutations –
mutations within a protein coding
sequence that do not affect the
amino acid sequence.
Nonsynonymous mutations –
mutations within a protein coding
sequence that alter the amino
acid sequence.
Wo r k b o o k
Lesson 3.2
Mutations occurring during DNA replication and mitosis
Mutations caused by the errors that occur during DNA replication or mitosis are limited to cells that are
actively dividing. Most cells that are terminally differentiated are no longer dividing, and are therefore
protected from these kinds of errors. However, stem cells and progenitor cells that are still dividing are
capable of developing mutations each time DNA
is replicated.
Normally, DNA polymerase is very accurate and
the DNA repair proteins are vigilant to identify
mistakes of DNA replication. As a result, the
normal mutation rate is only approximately 175
mutations total per duplication of the genome.
Most often, cells that accumulate mutations will
die, because they prevent the cell from being
a productive member of the cell community.
Most of the remaining mutations will have no
observable effect on the cell. These neutral
Figure 2: A gene fusion is formed when
mutations typically occur in sequences that do
the ends of chromosome 9 and chromosome
not encode proteins, or, if they do occur in coding
22 recombine, forming a longer chromosome
sequences do not alter the protein sequence.
9 and shorter chromosome 22. This forms
These so-called synonymous mutations are
the bcr-abl gene fusion, which is a hyperactive
possible because each amino acid has more
form of two proto-oncogenes.
than one codon. Most mutations a cell acquires
will be neutral: Only 2% of the genome encodes
proteins, so the chances of a mutation changing amino acid sequence (so-called nonsynonymous
mutations) and affecting cell behavior are very low. Moreover, the types of acceptable errors in DNA
replication is very limited. Hence development of mutations In a cell is a very slow and rare process.
However, if a random mutation compromises cell cycle control mechanisms (e.g. DNA repair proteins,
Rb, or p53), then the cell will begin to divide rapidly, thereby increasing the number of mutations that the
cell can accumulate. In fact, the mutations accumulated in tumors can increase by as much as 100,000
mutations per cell compared to normal cells.
Errors in mitosis are also relatively rare in normal cells, but these also will increase if cell cycle control
mechanisms are damaged. These errors of mitosis may lead to chromosomes inappropriately mixing
together, a process called chromosome recombination. When chromosomes recombine, they may
MC Questions:
4. Which of the following is the MAIN
difference between germline and
somatic mutations?
aa. Germline mutations cannot
affect gene expression.
bb. Germline mutations do not
cause transformation.
cc. Somatic mutations cannot be
inherited.
dd. Somatic mutations cannot alter
sequence of tumor suppressor
genes.
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5. True or False: Most mutations that
occur in a cell cause cell death.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
Chromosome recombination
– the process by which portions
of different chromosomes are
mixed together.
Gene fusion – a mutant gene
that is formed by two genes that
were previously separate were
joined through chromosome
recombination.
Point mutation – a change
in a single nucleotide of a DNA
sequence.
Single nucleotide
polymorphism (SNP) – a type
of mutation where only a single
nucleotide is altered – either
inserted, deleted, or substituted.
Wo r k b o o k
Lesson 3.2
create new types of genes by merging portions of
two genes together into one gene. A notable example
of this process, called a gene fusion, involves
chromosomes 9 and chromosome 22 swapping
portions of their chromosomes, producing a fusion of
two proto-oncogenes bcr and abl. This fusion (bcr-abl)
is responsible for causing a specific type of leukemia, as
well as being involved in the development of many other
types of cancer.
Mutations caused by agents in the environment
While mutations caused by DNA replication and mitosis
are limited to dividing cells, environmental mutagens can
cause mutations in any cells that are exposed to them
(i.e. both dividing and terminally differentiated cells).
While both replicating and non-replicating (terminally
Figure 3: Ultimate carcinogens
can chemically bind to DNA bases.
differentiated) cells are susceptible, replicating cells are
This affects how DNA polymerase
particularly vulnerable since environmental mutagens
detects the sequence, and leads to
may also promote errors of DNA replication and mitosis.
mutation of DNA.
Most exposed surfaces of our body are composed of
terminally differentiated epithelial cells; if these cells
are mutated by mutagens, they are easily killed and replaced by the epithelial progenitor and stem cells
buried just beneath them deeper in the tissue. Stem and progenitor cells are harder to replace if they
are mutated, so mutagens that can penetrate deeper into the tissue can have more profound effects in
causing cancer.
Perhaps the most common chemical mutations are stimulated by the reactive oxygen species (ROS)
that are produced when oxygen is metabolized in cells. When DNA bases such as guanidine (G) are
exposed to ROS they undergo a chemical reaction called oxidation, which produces 8-oxo-guanine. DNA
repair proteins incorrectly identify this base as a thymidine nucleotide and convert the G to a T. This type
of mutation in one nucleotide is called a point mutation. Another name for a point mutation is a single
nucleotide polymorphism (SNP). SNPs are any single base mutation such as when a single base is
added, removed, or substituted in a DNA sequence. UV radiation causes SNPs by chemically linking
thymidines together. DNA repair proteins then replace these thymidines with an adenine nucleotide.
Carcinogens, such as those found in tobacco, can bind DNA and cause damage (see Figure 3). Modification of DNA sequences by carcinogens leads to errors in DNA repair, which may make the cell more
susceptible to more mutations, particularly if that mutation occurs in a DNA repair protein.
MC Questions:
6. If random mutations are rare, why
do cancer cells typically have
thousands of mutations?
aa. Cancer cells are exposed to
more carcinogens.
bb. Epithelial cells have less efficient
DNA repair proteins.
cc. Most mutations are neutral
mutations.
dd. One key mutation leads
to accumulation of many
mutations.
7. How does carcinogen exposure
lead to DNA mutations? (Circle all
correct.)
aa. DNA repair proteins cannot
repair chemically altered
nucleotides.
bb. DNA polymerase cannot
recognize chemically altered
nucleotides.
cc. Carcinogens chemically modify
nucleotides.
dd. Carcinogens bind to DNA
polymerase.
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LESSON READINGS
Effects of DNA mutations on gene function
MC Questions:
In many cases, the types of mutations a cell must acquire to become transformed are very specific and
very rare. The random DNA mutations due to carcinogens or errors of DNA replication or mitosis are
rarely preserved in a cell, and the affected cells are usually killed through apoptosis
8. Which of the following mistakes are
caused by carcinogens? (Circle all
correct.)
aa. Gene fusions.
bb. Germline mutations.
cc. Point mutations.
dd. Somatic mutations.
Firstly, the mutations must only occur in a subset of genes and must be just the right types of mutations.
In previous lessons we have discussed how mutations of proto-oncogenes to form oncogenes and of
tumor suppressor are necessary for cellular transformation to occur. Furthermore, they must be just the
right type of mutations – i.e. the mutations must hyperactivate proto-oncogenes and inactivate the tumor
suppressor genes. Mutations that inactivate proto-oncogenes or hyperactivate tumor suppressor genes
will not lead to cancer, and will most likely lead to cell death.
However, if the cell has acquired just the right combination of mutations in tumor suppressor genes and/
or proto-oncogenes, it may be able to avoid death by apoptosis. Accumulation of DNA mutations that
cause a normal cell to become a tumor is just the first step of many physiological changes a transformed
tumor cell has to make on its path to becoming a cancer cell. One relevant DNA mutation is not enough
to cause cell transformation, rather it has been estimated that a minimum of 3-6 key DNA mutations are
necessary. It is important to realize that while all these mutations are required, cells do not all acquire
them in the same order, and differences between the order in which key mutations are acquired can lead
to key differences between individual tumors and cancers, such as how quickly they can spread from the
primary site to different tissues.
Wo r k b o o k
Lesson 3.2
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9. Which of the following is a type
of mutation that will promote
transformation? (Circle all correct.)
aa. Hyperactivation of protooncogene.
bb. Inactivation of proto-oncogene.
cc. Hyperactivation of tumor
suppressor gene.
dd. Inactivation of tumor suppressor
gene.
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STUDENT RESPONSES
Describe 2-3 types of DNA mutations and explain why most DNA mutations result in death of the cell. _____________________________________________________________________________________________________
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Wo r k b o o k
Lesson 3.2
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93
TERMS
TERM
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.2
DEFINITION
BRCA1
A tumor suppressor gene involved in DNA repair, whose mutated form is associated with breast and ovarian
cancer as well as other cancers.
BRCA2
Another tumor suppressor gene involved in DNA repair, whose mutated form is associated with breast and
ovarian cancer as well as other cancers.
Chromosome
recombination
The process by which portions of chromosomes are mixed together forming variants of sequence within
each chromosome.
Gene fusion
A mutant gene that is formed by two genes that were previously separate were joined through chromosome
recombination.
Germline mutation
Any detectable mutation or variation of DNA present within germ cells that is inherited by offspring of that
individual.
Mutagen
Any chemical or agent that is capable of mutating DNA sequence.
Neutral mutations
Mutations that do not affect the ability of a cell to function or survive.
Nonsynonymous
mutations
Mutations within a protein coding sequence that alter the amino acid sequence.
Point mutation
A change in a single nucleotide of a DNA sequence.
Single nucleotide polymorphism (SNP)
A type of mutation where only a single nucleotide is altered – either inserted, deleted, or substituted.
Somatic cell
Any cell that forms the body of an organism that is not a germ cell.
Somatic mutation
A change in DNA sequence of a cell that is not inherited by the offspring.
Synonymous mutations
Mutations within a protein coding sequence that do not affect the amino acid sequence.
Transformation
The process by which a cell acquires characteristic of a cancer cell.
94
LESSON 3.3 WORKBOOK
How can the immune system
behave as a carcinogen?
DEFINITIONS OF TERMS
Inflammation – the immune
response to infection, injury, or
irritation that results in pain, redness, and swelling.
Transforming viruses – a virus
that promotes the change in size,
shape, and growth of a cell such
that it behaves like a transformed
cell.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.3
In the previous lesson we learned how errors of DNA replication cause mutations
and transform cells. We learned that mutagens able to mutate DNA can be
carcinogens. However not all carcinogens are mutagens; some increase the
frequency of random DNA mutations by causing cells to hyperproliferate. In this
lesson we will learn how chronic inflammation can behave like a carcinogens
stimulating cells to hyperproliferate and increasing the chance they will acquire
mutations that will lead to transformation.
Pathogens and inflammation in cell transformation
In the previous lesson we learned about how mutagens can directly modify DNA sequences and promote
cell transformation. However, not all carcinogens are mutagens, some carcinogens induce cells to
hyperproliferate and as a consequence increase the chances that cells will acquire mutations that lead to
transformation.
How does cell hyperproliferation lead to transformation? Cells that are hyperproliferating are less able
to repair errors in DNA replication and during mitosis. Hence the likelihood of them acquiring a relevant
mutation to a proto-oncogene or a tumor suppressor gene leading to transformation is also increased.
The two major ways that agents promote hyperproliferation is through viral infection or activation of
inflammation.
In Unit 1 we learned how Peyton Rous identified Rous Sarcoma virus as the cause of chicken tumors
nearly 100 years ago. But the mechanism by which viruses work has only recently been discovered. We
now know that as part of their life cycle viruses promote dividing cells to hyperproliferate so they can infect
more cells and produce more virus. As the cells hyperproliferate the rate at which mutations accumulate
accelerates and transformation results. Viruses that promote hyperproliferation and transformation are
therefore called transforming viruses. Normally viruses that use the host cell machinery to replicate their
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1. Which of the following is a way that
carcinogens can transform cells?
(Circle all correct.)
aa. Directly mutate DNA.
bb. Activate hyperproliferation.
cc. Inhibit the immune system.
dd. Degrade stromal tissue.
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LESSON READINGS
genome weaken the cell so that it bursts and dies when virus exits the cell. Transforming viruses are able
to bury their genome in the host cells’
DNA, so that it is able to replicate without
killing its host or exposing itself to the
host’s immune system. Both DNA and
RNA viruses can be transforming, but the
strategies they use are different.
RNA viruses
RNA transforming viruses resemble
HIV. They replicate their genome using
reverse transcriptase and then insert the
DNA version of their genome into the
cell’s genomic DNA, as retrotransposons
do too. Cell transformation can occur
Figure 1: Transforming viruses (tumor virus)
can replicate their own genome by replicating the
either because the virus genome itself
cell they are infecting, rather than replicating their
encodes regulatory sequences that
genome in a traditional way and causing cell lysis.
promote over-expression of protooncogenes, or because the virus genome
carries an oncogene itself, like the Rous Sarcoma virus does – it carries the oncogene src.
Another way that RNA viruses can promote transformation is by inserting their genome within the protein
coding sequence of a tumor suppressor gene. This will disrupt the expression of the tumor suppressor
genes, and will also make the cell prone to hyperproliferate, leading to transformation.
This strategy of viral replication leading to cell transformation is so effective that sometimes viruses
STEAL host proto-oncogenes! As we learned in Unit 1, the Rous Sarcoma Virus (RSV) forms tumors
in chickens because it carried the src oncogene, which it had stolen from some host chicken way back
in evolutionary history. The src proto-oncogene found in normal chicken cells inhibits the cell cycle, but
the src oncogene carried by RSV has been mutated so that whenever the virus infects a chicken cell it
activates cell proliferation and forms tumors (called sarcomas). Again, this enables the virus to replicate
itself without being detected by the chicken immune system.
Wo r k b o o k
Lesson 3.3
The list of retroviruses that have stolen proto-oncogenes is long. In normal cells these proto-oncogenes
act at every stage in the transmission of a growth signal from the surface of the cell via a receptor through
transduction proteins to the nucleus. In each case the normal proto-oncogene found in a cell inhibits
some aspect of proliferation, while the oncogene stolen by the virus has been mutated to stimulate
proliferation, thereby increasing virus infectivity. Given how well this strategy works in a number of different
MC Questions:
2. Which of the following explains why
viruses transform cells? (Circle all
correct.)
aa. Faster replication cycle.
bb. Escape from immune system.
cc. Not have to find a new host.
dd. Easier to kill cells.
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3. Which of the following is a way that
RNA viruses can transform cells?
(Circle all correct.)
aa. Integrate into tumor suppressor
gene.
bb. Express protein that degrades
tumor suppressor genes.
cc. Express its own oncogene.
dd. Promote expression of protooncogene.
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animals, it is very surprising that only one retrovirus has been found that causes cancer in humans.
Clearly there are aspects of this biology in humans we still don’t understand.
DNA viruses
DEFINITIONS OF TERMS
Inflammatory response –
same as inflammation. The
immune response to infection,
injury, or irritation that results in
pain, redness, and swelling.
Wo r k b o o k
Lesson 3.3
Most RNA viruses have very small genomes; in contrast, because DNA is more stable than RNA, DNA
viruses can have relatively large genomes containing more genes. Hence, while transforming RNA
viruses have to either ‘modify proto-oncogenes/tumor suppressor genes or ‘steal’ host oncogenes,
transforming DNA viruses can just carry along genes that promote cell proliferation and allow them to
avoid immune detection. DNA tumor viruses can also promote hyperproliferation by inactivating tumor
suppressor proteins, most notably the Rb protein. As we learned in Unit 2 Rb is one of the most important
regulators of the cell cycle, because it controls the R transition point. Recall that Rb serves as a gatekeeper to control the cell cycle because once cells have passed the R point they are committed to the cell
cycle and no longer need extracellular growth signals.. The main goal of DNA tumor viruses is to inhibit
the Rb protein by any means necessary, thereby forcing the cell to enter the cell cycle. DNA viruses,
such as human papillomavirus (HPV) have proteins such as E7, which destroy Rb. This function of the E7
protein is seen in 99.7% of all cervical cancers.
The immune system and cell transformation
Pathogens such as the transforming viruses can transform cells directly, but other pathogens as well as
many carcinogens can promote cell transformation indirectly, by activating the inflammatory response of
the immune system. Inflammation is the immune system’s front line defense against pathogens, damaged
cells or irritants, and is associated with swelling, pain, redness, and heat. During inflammation, blood
vessels at the site of damage/infection will open up and allow immune cells to enter the tissue. These
immune cells increase the blood flow at the site of damage, which causes the increases in redness and
heat. These blood vessels are also more leaky, and release contents such as immune cells, proteins,
and water (which increases swelling and pain caused by swelling). As we shall learn in the next Unit,
the growth of leaky blood vessels at the site of damage/infection allows cancer cells to spread into the
bloodstream and metastasize to other organs.
But inflammation not only promotes the ability of cancer cells to metastasize to other organs, it can also
lead to transformation of normal cells to tumor cells. For example, many types of stomach and liver
cancers are due to infection with pathogens. Stomach cancer is caused by the bacterium H. pylori, while
liver cancers caused by infections from the hepatitis B and C virus as well as the liver fluke (a type of
parasitic worm). These pathogens activate cancer by promoting tissue inflammation. Other carcinogens
that activate inflammation include: alcohol, radiation, and environmental pollutants.
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4. True or false: Src protein encoded in
the genome of a virus can cause cell
transformation.
aa. True.
bb. False.
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5. Which of the following inflammatory
responses promotes progression of
cancer? (Circle all correct.)
aa. Activation of pain receptors.
bb. Increase of blood flow.
cc. Growth of blood vessels.
dd. Killing of damaged cells.
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DEFINITIONS OF TERMS
Cytokines – signaling proteins
released by immune cells that
affect the behavior of other cells.
Tumor necrosis factor α
(TNF-α) – a signaling molecule
secreted primarily from immune
cells, but also from other cells,
that is the primary activator of
inflammatory response.
Chronic infections – an
infection that is persistent and
never fully cleared by the immune
system.
Adipose cells – cells that are
specialized to store fat in the
body.
Inflammation promotes cell transformation in two ways. By killing off infected or damaged cells, the
inflammatory response destroys tissue structure, exposing stem and progenitor cells to other carcinogens
that can mutate DNA directly. Inflammation can also cause secretion of important signaling proteins called
cytokines, which are essentially signals from immune cells that instruct other cells how they should
behave. These cytokines can induce hyperproliferation. One of the most potent cytokines in inflammation
is tumor necrosis factor α (TNF-α). TNF-α is a signaling molecule that is primarily intended to recruit
immune cells at a site of infection. TNF-α is intended to signal only to immune cells, however liver and
stomach carcinomas can also receive TNF-α signals, leading to activation of the NF-кB pathway. In Unit
2 we learned that the TNF-α/NF-кB pathway which
promotes the growth and survival of cells, is often
active in tumor cells.
Pathogens such as H. pylorii, hepatitis B and C
viruses, and liver flukes cause chronic inflammation,
because the infection is never fully cleared, despite
the continuous activation of inflammatory response.
Another chronic inflammatory state is seen in individuals who are obese. Adipose cells, the cells that store
fat in the body, increase in size and number during
obesity. These cells also constantly secrete TNF-α, so
increase numbers of adipose cells may promote the
chronic inflammation that can lead to cancer.
Altogether, carcinogens that promote inflammation or
hyperproliferation of cells are responsible for promoting cell transformation by increasing the chance that
random DNA mutations will occur.
MC Questions:
6. Which of the following is an outcome
of TNF-α signaling? (Circle all
correct.)
aa. Recruitment of immune cells.
bb. Recruitment of adipose cells.
cc. Activation of NF-кB.
dd. Clearance of pathogen from
infected tissue.
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Figure 2: Prolonged infection by
Hepatitis B or C viruses or excessive
alcohol consumption leads to progression of disease and liver cancer caused
by inflammation.
7. Why is obesity associated with
cancer? (Circle all correct.)
aa. Obese people have weak
immune systems.
bb. Obese people secrete more
TNF-α.
cc. Obese people experience
chronic inflammation.
dd. Obese people more susceptible
to transforming virus infection.
Wo r k b o o k
Lesson 3.3
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STUDENT RESPONSES
Smoking while drinking alcohol has been shown to increase the risk of developing cancer more than smoking alone. Can you
explain a way in which smoking and drinking could increase the chances of cell transformation more than smoking alone?
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Wo r k b o o k
Lesson 3.3
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.3
DEFINITION
Adipose cells
Cells that are specialized to store fat in the body.
Chronic infections
An infection that is persistent and never fully cleared by the immune system.
Cytokines
Signaling proteins released by immune cells that affect the behavior of other cells.
Inflammation
The immune response to infection, injury, or irritation that results in pain, redness, and swelling.
Inflammatory response
Same as inflammation. The immune response to infection, injury, or irritation that results in pain, redness,
and swelling.
Tumor necrosis factor α
(TNF-α)
A signaling molecule secreted primarily from immune cells, but also from other cells, that is the primary
activator of inflammatory response.
Transforming viruses
A virus that promotes the change in size, shape, and growth of a cell such that it behaves like a transformed
cell.
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LESSON 3.4 WORKBOOK
How do cancer cells cheat death?
DEFINITIONS OF TERMS
The previous three lessons we explored in some detail on how DNA is organized
and what kind of mutations are necessary to cause the cell transformations that result in hyperproliferation. But changing a normal cell into a tumor cell involves more
than just causing it to replicate more. Tumor cells also have significantly extended
life-spans and some are even immortal. This lesson investigates how tumor cells
are made immortal by examining how cells normally age and how tumor cells
subvert the aging process.
Immortality – the ability of cells
to divide indefinitely.
Cell aging and immortality: telomeres
Telomeres – a section of repetitive DNA sequence at both ends
of a chromosome.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.4
Henrietta Lacks was diagnosed with an aggressive form of cervical
cancer in 1951 and died a few months later, but the cells isolated
from her tumor are not only still in existence, but are still able to divide
vigorously. These so-called HeLa cells have been used by labs around
the world, and continue to be an important resource for scientists who
want to study how cancer cells behave. The ability of cancer cells
like these HeLa cells to grow indefinitely is called immortality. In this
lesson we shall discuss the mechanisms that cause normal cells to
age and die and how they are altered in tumor cells.
Figure 1: Henrietta
We have already learned how the lifespan of a cell is often cut short
Lacks. Though she died in
by the DNA mutations it accumulates. But another factor also controls
1951 of cervical cancer,
how cells age and when they die. This factor is the protective elements
her cancer cells are still
on the end of chromosomes called telomeres. Every time a cell
alive.
divides it must replicate every one of its chromosomes. This causes a
problem: DNA is replicated by the enzyme DNA polymerase that binds
to the existing chromosome and then works its way along copying the sequence by adding new nucleotides to build a new strand of DNA. DNA polymerase needs 10 nucleotides to hold onto as it performs its
building operation. The problem comes once the DNA polymerase reaches the end of the chromosome.
MC Questions:
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1. What is the property of cells that
allow them to divide indefinitely?
aa. Apoptosis.
bb. Immortality.
cc. Telomere shortening.
dd. Transformation.
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LESSON READINGS
DEFINITIONS OF TERMS
Double-strand break – a condition of DNA damage where both
strands of the double helix are
cleaved.
Suddenly it has nothing
to hold onto, so it can’t
add on the last few
nucleotides. Obviously
if the chromosome
loses a few nucleotides
every time it replicates
there will eventually come a time when
those nucleotides
Figure 2: Shortening of telomere ends leads to damage to
are part of something
chromosome structure and errors of separation during mitosis.
important like a
These errors eventually lead to apoptosis of cells with short
telomeres.
coding sequence of a
gene, which could be
disastrous for the cell.
Fortunately the chromosome ends are protected by repeating sequences of nucleotides that don’t code
for anything important. These repeating sequences are called telomeres.
Each time the cell divides and the chromosomes replicate, the end of the telomeres aren’t copied
because DNA polymerase has nowhere to attach to. But this isn’t important because the telomeres don’t
code for anything important and are essentially there for insulation. This is not a perfect fix: Because the
telomeres won’t be replicated fully either they too will eventually become too short to protect the ends of
the actual chromosome DNA, as we described before. At this point the ends of the chromosomes will fuse
together and the cell will go into crisis and die by apoptosis.
Cells respond the same way whenever chromosome ends are exposed like this, whether this is caused
by telomere shortening or by any of the chemicals that can break both strands of DNA to fracture the
chromosome (this is called a double-strand break) The same DNA repair proteins that sense the
unprotected, fused ends that occur after telomere aging cause the cells to enter apoptosis.
While telomere length can give some idea as to how many replications a cell has undergone it cannot be
used to precisely tell how many replications a cell has undergone. This is because how much telomere is
lost at each replication varies from chromosome to chromosome and cell to cell. Nevertheless the average length of telomeres is strongly correlated with aging, a concept we will explore further later.
Wo r k b o o k
Lesson 3.4
MC Questions:
2. Which of the following explains
why telomeres are on the ends of
chromosomes? (Circle all correct.)
aa. To protect the ends of
chromosomes.
bb. To prevent double-strand break
repair.
cc. To activate the apoptosis
pathway.
dd. To progress the cell through
mitosis.
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DEFINITIONS OF TERMS
Telomerase (TERT) – an enzyme similar to reverse transcriptase that adds DNA to telomere
ends maintaining their length
across multiple cell divisions.
Alternative lengthening of
telomeres (ALT) – an alternative
pathway that some cancer cells
use to replace lost telomere ends
by using DNA recombination.
Preventing telomere shortening: telomerase
MC Questions:
We can think of telomeres as a ‘generational clock’ that shortens during each round of replication, and
once telomeres get too short the cell dies. Hence one effective step to transforming a cell so that it is
immortal would be to prevent the telomere shortening. Transformed cells have found a way to do this by
expressing an enzyme that is able to keep telomeres long. This enzyme is called telomerase (TERT).
3. True or False: It is possible to
determine exactly how old a cell
is based upon the number of
telomere repeats at the ends of
chromosomes.
aa. True.
bb. False.
Telomerase works like reverse transcriptase
(of retrotransposons and HIV fame): it first
makes an RNA template and then uses the
RNA template to make DNA, which can insert
into the genome – in this case onto the ends of
telomeres. Telomerase does this very efficiently,
but it shut off in normal cells that we do want to
age and die. Not surprisingly transformed cells
reactivate telomerase to keep their telomeres
long and protect the cells from aging. In fact
85-90% of all human tumors express telomerase
at high levels, confirming how important it is for
tumors to overcome normal cellular aging. The
remaining 10-15% of tumor cells that do not used
telomerase to prevent telomere shortening have
devised their own solution: These cells devise
extend telomere ends in a different way called
alternative lengthening of telomeres or ALT.
ALT uses DNA recombination to elongate the
ends of chromosomes.
Figure 3: Telomerase replaces lost
telomere ends by using hTR RNA
template to extend DNA sequence.
Telomerase in normal cells
Wo r k b o o k
Lesson 3.4
Telomerase plays an important role in normal cells, specifically those cells that divide frequently and can’t
afford to age and die, namely stem cells and progenitor cells. We learned in Unit 2 that fully differentiated
cells, like those in the epithelium, are generated from stem cells and progenitor cells by the process of
differentiation. Differentiation allows cells to acquire specialized functions and at the same time they often
lose other functions like the ability to replicate. So when a differentiated epithelial cell becomes damaged
or dies because it is exposed to the external environment or carcinogens it is replaced from a store of
progenitor cells sitting deep within the epithelium. This store of stem cells and progenitor cells are critical
4. Which of the following is a way for
cancer cells to avoid the problem
of telomere shortening? (Circle all
correct.)
aa. Overexpressing telomerase.
bb. Decreasing replication rate.
cc. Using the ALT pathway.
dd. Epigenetic control of DNA
replication.
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DEFINITIONS OF TERMS
Self-renewal – the ability of a cell
to replicate itself indefinitely and
identically through mitosis.
for the epithelium to survive constant exposure to damage, so they must be protected
from aging and dying. To do this they
express telomerase at levels, which more
or less protects the telomeres from shortening. Eventually however telomerase in stem
cells and progenitors is not sufficient to
prevent telomere shortening and so these
cells too will age and die. This is particularly
noticeable in the epithelium of the nose.
The nose epithelium produces the neurons
that are responsible for the sense of smell
and is constantly under attack from environmental toxins. Stem cells in the nose
are constantly producing new neurons (as
well as new epithelium) to replace cells that
are damaged and killed. Eventually these
stem cells are exhausted and as a result
our sense of smell decreases markedly as
we age.
5. What happens to the average
telomere length of our cells as we
get older?
aa. It gets longer.
bb. It gets shorter.
cc. It does not change.
dd. There are no telomeres on DNA
when we are old.
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Figure 4: Stem cells rarely have to undergo
mitosis, but progenitor cells must constantly
replicate in order to replace lost or damaged
differentiated cell. The process of aging results
in fewer and fewer undifferentiated stem cells,
leading to shorter telomere ends and older cells.
At this point we can differentiate between
cellular aging – which occurs when telomeres get too short to protect the ends of
chromosomes - and bodily aging, which occurs when stores of stem cells in the body are depleted. The
stem cells that remain may have normal telomeres, there just aren’t enough of them to effectively replace
damaged cells. This is why stem and progenitor cells are protected from environmental factors by being
stored beneath the body surface, and why sunburns that damage the deep epithelium are so much more
dangerous than those only damaging the surface.
Wo r k b o o k
Lesson 3.4
MC Questions:
Exposure to carcinogens is problematic for two reasons: First, carcinogens that damage the DNA of
progenitor or stem cells may transform these cells. Second, if carcinogen exposure does not promote
transformation directly it may lead to apoptosis of these cells. Whenever a stem or progenitor cell
apoptoses the reserve of cells that help repair damage is depleted. This is why exposure to carcinogens
accelerates aging, and why people who smoke frequently often look older than they actually are.
6. What is the normal function of
telomerase in cells?
aa. Aid in differentiation.
bb. Keep terminally differentiated
cells alive.
cc. Prevent stem cells from
becoming progenitor cells.
dd. Preserve the pool of stem and
progenitor cells.
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STUDENT RESPONSES
Describe one advantage and one disadvantage of having telomeres shorten each time a cell replicates.
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Wo r k b o o k
Lesson 3.4
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105
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.4
DEFINITION
Alternative lengthening of
telomeres (ALT)
An alternative pathway that some cancer cells use to replace lost telomere ends by using DNA
recombination.
Cell “lines”
A population of cells derived from a single cell and containing the same genetic makeup that can grow
indefinitely.
Double-strand break
A condition of DNA damage where both strands of the double helix are cleaved.
Immortality
The ability of cells to divide indefinitely.
Self-renewal
The ability of a cell to replicate itself indefinitely and identically through mitosis.
Telomeres
A section of repetitive DNA sequence at both ends of a chromosome.
Telomerase (hTERT)
An enzyme similar to reverse transcriptase that adds DNA to telomere ends maintaining their length across
multiple cell divisions.
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LESSON 3.5 WORKBOOK
How do cancer cells evolve?
In this unit we have learned how normal cells can be transformed so that they
stop behaving as part of a tissue community and become unresponsive to regulation. Once this transformation occurs and each individual cell in a tumor starts to
compete with other cells for limited resources. This lesson wraps up the unit by
exploring how each individual tumor cell evolves differently so that the end product
may be a tumor that is composed of many different kinds of cells with different
mutations and functions that are adapted to the environment.
Monoclonal and polyclonal tumors
In this unit we have learned how the random accumulation of critical DNA mutations can cause a normal
cell to transform itself into a tumor cell. We have learned about mutations to proto-oncogenes and tumor
suppressor genes that can allow cells to hyperproliferate and how mutations that permit telomerase
expression can prevent cell aging and death and allow cells to become immortal. We have also learned
about environmental carcinogens that damage DNA directly or that promote transformation by stimulating cells to proliferate and acquire mutations. We have learned how the immune system can act as a
carcinogen by promoting chronic inflammation. In each case we have learned about these behaviors by
focusing on individual cells. For this lesson we need to take a step back and consider transformed cells in
a population rather than singly. A single normal cell may give rise to a single transformed cell, but as soon
as that transformed cell hyperproliferates a number of times, each time acquiring mutations randomly, it will
not be long until the cells in the tumor look very different from each other.
Wo r k b o o k
Lesson 3.5
The fact that tumors are composed of multiple different populations of transformed cells has a huge influence on how the tumor as a whole will behave. Some transformed cells may eventually acquire mutations
that lead to apoptosis. Others may divide faster than normal. The process of cell transformation and the
road from benign tumor to malignant tumor and then to metastatic cancer is similar to evolution. And as in
evolution where the fittest survive, cells must compete with surrounding cells, both normal and transformed
for nutrients and resources so that they can grow within the confined space of the tissue.
MC Questions:
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1. Which of the following is an
immediate outcome of exposure to
carcinogens? (Circle all correct.)
aa. Cell death.
bb. Cell differentiation.
cc. Cell spread.
dd. Cell transformation.
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LESSON READINGS
DEFINITIONS OF TERMS
Monoclonal – a group of cells
produced from a single cell
by repeated cycles of cellular
replication.
Polyclonal – a group of cells
produced from multiple different
cells through repeated cycles of
cellular replication.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.5
Tumors that appear to be composed of
a single population of cells are said to be
monoclonal (the left hand side tumor in
Figure 1), whereas tumors that appear to be
composed of multiple different populations of
cells are said to be polyclonal (the right hand
side tumor in Figure 1). In reality a tumor
is highly unlikely to be monoclonal, for the
reasons outlined above, but it is not always
very easy to detect the different populations
of cells in a tumor from their DNA sequence
characteristics. First of all DNA sequencing
techniques are not yet sensitive enough
to detect very small numbers of cells of a
specific population in a large tumor, especialFigure 1: Two models of tumor formation.
ly if one type of cell is dominant. For instance,
if one population divides more rapidly, it may
swamp out other smaller populations, so the
tumor appears monoclonal. Additionally, as we learned in Unit 2, not all changes to cells that promote
transformation occur because the DNA sequence has changed. Epigenetic modifications to DNA will not
be detected by conventional sequencing techniques and will require more specialized methods to detect
acetylation and methylation for example. Hence while most tumors may appear to be monoclonal, they
are in fact, polyclonal.
Tumors can be polyclonal for many different reasons. First, they could have arisen from one cell of origin
that has acquired different genetic and non-genetic changes as it proliferates, as we discussed above.
Alternatively a tumor can arise from multiple different cells of origin. It is fair to say that the future of understanding the biology of cancer will depend on us being able to understand the true nature of different cells
in a tumor, both genetically and epigenetically.
We have learned that as tumors develop they become malignant by moving through the basement
membrane into the stroma. At that stage they go beyond simply being polyclonal, because they also begin
to incorporate non-cancerous cells into the tumor mass. For example, it is not uncommon to see cells of
the stroma (stromal cells) and immune cells within the tumor mass. In fact, as many as 90% of the cells in
a malignant tumor in the breast, colon, stomach and pancreatic tissues may be either stromal or immune
cells. This number goes as high as 99% in Hodgkin’s lymphoma, a cancer of the immune system. We
have learned that these normal cells can provide critical signals that help the cancer cells grow, survive,
evade the immune system, and spread through the bloodstream to surrounding tissues, and we will learn
more about this in the next unit.
MC Questions:
2. True or False: Tumors are composed
of multiple different types of cells
aa. True.
bb. False.
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3. Which of the following can be
incorporated into a pancreatic
tumor? (Circle all correct.)
aa. Immune cells.
bb. Neurons.
cc. Stromal cells.
dd. Stromal proteins.
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LESSON READINGS
DEFINITIONS OF TERMS
Selective advantage – any
property of a cell that gives it a
survival advantage over other
cells.
Selective disadvantage – any
property of a cell that gives it a
survival disadvantage over other
cells.
Selective pressure – any
external cause that reduces the
ability of cells to replicate.
Wo r k b o o k
Lesson 3.5
Selective pressure on tumor cells
MC Questions:
We have learned that a single mutation is not enough to transform a normal cell into a tumor cell, even if
that mutation is critical such as to a proto-oncogene. In fact a tumor cells needs a minimum of 3-6 critical
mutations in order to become stably transformed. Why so many? In order to answer this question we
need to examine how cancer cells need to be able to compete against other cells in the environment.
4. How many mutations are necessary
to transform a normal cell to become
hyperproliferative?
aa. 1
bb. 3
cc. 10
dd. 100,000
If we think about the process of
evolution in general, random mutations
confer benefits that promote survival
of some organisms at the expense of
others. Cancer cells behave in exactly
the same way. As they acquire random
mutations, those that make the cell
more efficient at growth and survival
will provide a selective advantage
to some cells over others. Conversely
random mutations that prevent growth
with provide a selective disadvantage. But why do some mutations
provide a selective advantage
whereas others do not? The reason
is because the external environment
provides selective pressures that
co-operate to prevent the limitless
growth of cancer cells, preventing the
selective advantage of whatever mutations they may have at any one time.
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Figure 2: Mutations can either increase the
chance of cancer by promoting survival or growth,
or promoting death. Cancer occurs by accumulation
of more pro-growth/pro-survival mutations than any
other type of mutation. Acquiring other mutations will
increase the chance the cell dies.
One common example of selective pressures is the availability of oxygen. Cancer cells that are dividing
rapidly will require a plentiful supply of oxygen to grow, and must compete with other cells that may have
the same mutations for a limited supply. One way in which a cell could gain a selective advantage in
response to this selective pressure would be to acquire a mutation so that it can divide rapidly even in low
concentrations of oxygen. In fact many cancer cells do change their metabolism in this way. The immune
system can provide another example of selective pressure. We have learned previously that the immune
system can behave as a carcinogen, but the immune system can also detect and kill cancer cells very
effectively. This role of the immune system is called immunosurveillance, and will be described more in
the next unit.
5. Which of the following can be
considered to be a selective
pressure? (Circle all correct.)
aa. p53 activation of apoptosis.
bb. Immunosurveillance.
cc. Cyclin activation.
dd. Telomere shortening.
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LESSON READINGS
DEFINITIONS OF TERMS
Immunosurveilance – the
principle that the immune system
is responsible for identifying and
killing cancer cells.
Clonal expansion – the process
by which a single cell replicates
to give rise to many other cells
within a population.
Clone – a single cell that gives
rise to many cells.
Wo r k b o o k
Lesson 3.5
Understanding the different selective pressures a cancer cell experiences makes it more evident why 3-6
mutations are necessary for a normal cell to transform stably into a cancer cell. For example, a mutation
in a proto-oncogene might lead to hyperproliferation, but then the activity of a normal tumor suppressor
gene would prevent that hyperproliferation and simply activate apoptosis. The cancer cell would gain a
selective advantage to this selective pressure if it then acquired a mutation in a tumor suppressor. But
even this would not be enough for stable transformation since the immune system is continually surveying
tissues for abnormalities (we will see how later). So the immune system will exert selective pressure on
the transformed cell, which could gain a selective advantage if it acquired a mutation that allowed it to
evade immune surveillance.
The ability of a highly proliferative, heavily mutated cell to escape immune surveillance is a key step in
tumor development. This step, which allows one cell with significant selective advantages to dominate
a tumor, at least in the short term is called clonal expansion. This dominant clone explains why many
tumors appear to be monoclonal in nature, even though they are composed of other cell types that did not
win the struggle for survival within the tumor.
It is important to realize also that not all cells acquire the same mutations in the same order. Hence a cell
that has already acquired mutations that will allow it to metastasize is primed and ready to go once it has
reached the clonal expansion stage.
Cancer evolution
Clonal expansion allows one choice cell that has acquired just the right set of mutations to dominate a
tumor in the short term. But development of cancer as a disease requires more selective advantages than
hyperproliferation and clonal expansion. Hyperproliferative cells are not the same as cancer cells. The
dominant clone now able to evade immune surveillance can grow happily in place, but oxygen supplies
are limited, so maybe the cell gains a selective advantage by acquiring a mutation to alter its metabolism.
But a different cell in the dominant clone that has now acquired a mutation enabling it to break through
the basement membrane will have more of an advantage, while yet another cell that can migrate into the
bloodstream and travel to distant locations will have even more. Finally the cell that can settle in a secondary location and grow there will be most successful in this evolutionary race. But as this secondary tumor
grows, selective pressures appear again. The traits of cancer cells are therefore in constant competition
with each other.
MC Questions:
6. Why do tumors appear to be
monoclonal in nature?
aa. They are monoclonal.
bb. One cell outcompetes its rivals.
cc. Immune system kills all but one
type of cell in a tumor.
dd. Only one cell in a tumor can
inactivate p53.
7. Why do cancer cells require multiple
mutations for transformation? (Circle
all correct.)
aa. Cells are in competition with
each other.
bb. At least 3 genes need to be
mutated to inactivate a signaling
pathway.
cc. Cells must avoid detection of
immune system.
dd. Multiple mutations inactivate
DNA repair mechanisms.
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LESSON READINGS
The environment that
a cancer finds itself in
is critical for how it will
evolve as a disease. We
learned in Lesson 3 of
this unit that cells that
are chronically infected
will experience chronic
inflammation that can lead
to cancer traits such as
hyperproliferation. Similarly,
tissues that are regularly
exposed to carcinogens
or toxic agents, provide
a selective advantage to
cancer cells as they grow
and spread to surrounding
tissues, because the
surrounding normal cells
are so weakened by the
carcinogen/toxin exposure.
8. Which of the following is a trait of
cancer cells? (Circle all correct.)
aa. Activate inflammation.
bb. Evade immune system.
cc. Growth.
dd. Adhere to blood vessels.
Figure 3: A normal cell progresses to a tumor by
becoming transformed and hyperproliferative. The
progression to cancer requires further mutations and
development of the ability to migrate through
surrounding tissue.
These past two units have described how a normal cell progresses through its life cycle and how specific
points of the cell cycle are particularly vulnerable to the kind of DNA mutations that can radically alter cell
behavior and affect cell function. These mutations turn a normal member of the tissue community into
a hyperproliferative tumor cell that can no longer respond to regulation. The next unit will shift from the
cell-centered perspective of cancer to the an investigation of the interactions between cells, tissues, and
organs that allow transformed cells to become disease-causing malignant tumors and metastatic cancers.
Cancer is a disease of evolution, and as we shall see in the next unit, the environment of the cancer plays
an important role in the development of full-blown disease.
Wo r k b o o k
Lesson 3.5
MC Questions:
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STUDENT RESPONSES
Describe the steps necessary for a normal cell to become a cancer cell, keeping in mind what types of genes must be mutated,
how they must be mutated, and how the mutations are a product of evolution.
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Wo r k b o o k
Lesson 3.5
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112
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.5
DEFINITION
Clonal expansion
The process by which a single cell replicates to give rise to many other cells within a population.
Clone
A single cell that gives rise to many cells.
Immunosurveilance
The principle that the immune system is responsible for identifying and killing cancer cells.
Monoclonal
A group of cells produced from a single cell by repeated cycles of cellular replication.
Polyclonal
A group of cells produced from multiple different cells through repeated cycles of cellular replication.
Selective advantage
Any property of a cell that gives it a survival advantage over other cells.
Selective disadvantage
Any property of a cell that gives it a survival disadvantage over other cells.
Selective pressure
Any external cause that reduces the ability of cells to replicate.
113
Unit 4:
Unit 4: Introduction
Where are we heading?
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a 'normal' cell?
Unit 3: How do normal cells become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How is cancer diagnosed and treated?
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In Unit 4 we'll take a step back and a broader
approach to looking at cancer as a disease.
Lesson 4.1 will explore the difference between benign and malignant
tumors and give you the opportunity to learn how to differentiate
between them. Lesson 4.2 grapples with the concept of metastasis
- that is that tumors often don't stay in one place but migrate in the
bloodstream to find new homes. Lesson 4.3 investigates what factors
a migrating, metastatic cell needs in order to settle into a site and
form a secondary tumor. Lesson 4.4 explores the role of the immune
system in tackling and neutralizing more than 95% of cancers before
we are even aware of them!
114
LESSON 4.1 WORKBOOK
What is cancer?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
Hyperproliferation – the rapid
growth of cells that is unresponsive to regulatory signals
Focal Tumor – a tumor that is
localized to a specific part of a
tissue, commonly the epithelium.
Malignant Tumor – a tumor that
has migrated out of the epithelium and into the stroma of the
tissue.
Disseminated symptoms –
symptoms that extend beyond
the local distribution of the
primary tumor.
Metastasis – the spread of malignant tumor cells through blood/
lymph vessels to other parts of
the body.
Wo r k b o o k
Lesson 4.1
In the previous two units we have examined the mutations that cause cell behavior
to become abnormal so that cells hyper-proliferate, become immortal and form
tumors. But tumor formation is only the first stage in developing cancer, and not
all tumors will become malignant. For a benign tumor to cause disease it needs to
acquire the ability to migrate beyond the site where it initially developed. In this lesson we will begin to explore how a benign tumor becomes malignant, and the rest
of this unit will focus on cancer as a disease.
From benign to malignant: what is cancer?
We have seen how cells in normal tissue interact as a community. But if a cell acquires mutations that
affect critical proteins such as proto-oncogenes and tumor suppressors it turns its back on its community
and becomes unresponsive to regulatory signals. Instead it starts to hyper-proliferate and becomes
immortal. The primary tumor that forms as a result is called a focal tumor
because it is confined to a specific place, usually within the epithelium.
Focal tumors may be large but while they are confined to the epithelium
and don’t cause disseminated symptoms of disease they are considered
benign.
For instance, the salivary gland tumor depicted in Figure 1 is very large
and unattractive and probably quite uncomfortable to live with, but
because it is confined within the salivary gland epithelium it is considered
benign. If cells in a benign focal tumor acquire additional mutations that
enable them to spread beyond the epithelium into the stroma they are
considered malignant and are able to cause disseminated symptoms.
The ability of tumors to spread beyond the stroma into the bloodstream
and lymph and to secondary organs is known as metastasis.
Figure 1: This benign
salivary gland tumor
may be large, but it
is focal and benign
and therefore not
cancerous.
Because of this definition even a tiny tumor, like that depicted in
Figure 2, is considered malignant because it has spread into the stroma and will be able to cause
MC Questions:
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1. Which of the following is most
important in determining whether a
tumor is cancerous?
aa. Size of the tumor.
bb. Shape of the tumor.
cc. Color of the tumor.
dd. Whether the tumor is spreading.
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115
LESSON READINGS
DEFINITIONS OF TERMS
Melanoma – A malignant tumor
of the skin that is often asymmetrical and multicolored.
Mole – A focal tumor of the skin
disseminated symptoms. We know that the transformation from
benign, focal skin tumor (called a mole) into a malignant, metastasized
tumor (called a melanoma) has occurred because of changes in the
tumor’s appearance: Benign moles are most often symmetrical and
evenly colored, while malignant tumors, like the one in Figure 2 are
asymmetrical and multicolored even if they are small. The purpose of
Figures 1 and 2 are to emphasize the point that the size of the primary
tumor does not correlate with the severity of the disease it may cause.
The important characteristic is whether or not the tumor has acquired
the ability to spread.
As tumors transform into cancer: grade
and stage
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Figure 2: This
is a skin cancer. Its
characteristics indicate
that it has acquired the
capacity to metastasize
to surrounding tissue.
Clearly not all tumors are visible on the surface of the body, so we
need another way to identify whether a primary tumor is benign or malignant. Two main criteria are used
clinically: tumor grade and stage.
Cancer grade – a classification
system that characterizes cancer
cells based upon how similar they
look to their normal counterparts.
Cancer stage – a classification
system that describes the extent
to which a tumor has spread.
Wo r k b o o k
Lesson 4.1
MC Questions:
Figure 3: A tumor’s
grade defines how different
the cells have become
from normal cells. Grade
1 are most normal, while
higher-grades look more
abnormal.
A tumor’s grade depends on the appearance of the tumor cells
themselves. As we have learned, tumors occur when cells abandon their normal functions and proliferate uncontrollably. As they
do this they also abandon their normal appearance. For instance
different kinds of epithelial cells have different appearances
that reflect their different functions in the body. Once epithelial
cells start to form tumors they lose these distinctive shapes and
become much more like cells that have not fully differentiated.
The grade of a tumor therefore reflects how different the cells in
the tumor are from normal cells. Hence cells in a high-grade tumor
will have changed so much in size and/or shape that they don’t
look normal at all. Grading scales vary depending on the tumor in
question. For example breast tumors are graded on a 1-3 scale
with a grade 1 indicating a focal tumor and a grade 3 indicating
that the cells look so abnormal they probably have acquired the
potential to spread to other tissues and cause disease. A diagnosis of grade 4 is made when evidence that the tumor has spread
has been found. In contrast prostate tumors are graded on a 2-10
scale, but using the same principle – low looks more normal, high
looks most abnormal.
2. True or False: It is impossible to
tell whether a tumor is benign or
malignant.
aa. True.
bb. False.
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3. Which of the following is
characteristic of a cancerous tumor?
aa. High stage.
bb. Symmetrical tumor.
cc. Low grade.
dd. All of the above.
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116
LESSON READINGS
DEFINITIONS OF TERMS
Lymph nodes – organs of the
lymphatic system that collect and
process lymph fluid from nearby
organs.
A tumor’s stage depends on how much the
tumor has spread to surrounding tissues.
Again the scale reflects the extent to which
spread has occurred, generally within a
5-point system. Stage 0 and Stage I are
therefore focal, benign tumors that have
not spread into surrounding tissues. Stage
II tumors have begun to spread into the
stroma. Stage III are more metastatic,
and have spread through the blood/lymph
to nearby lymph nodes, while Stage
IV tumors have also spread beyond the
lymph nodes to other organs.
Both stage II and stage IV are considered
malignant. We will explore the importance
of spreading to lymph nodes in the next
few lessons.
4. True or False: Larger tumors
are more likely to have cells that
randomly evolve to acquire the
capacity to spread than smaller
tumors.
aa. True.
bb. False.
Figure 4: A tumor’ stage defines how far it has
spread. On a 4-point scale, stage 0/1 indicates a
focal tumor that has not spread. Stage 2 indicates
a larger focal tumor that has begun to spread.
Stage 3 indicates the tumor has spread to nearby
lymph nodes. Stage 4 indicates full metastasis to
surrounding organs.
It is worth noting that while bigger tumors
are more likely to have acquired enough mutations to spread, very small tumors can also metastasize, as
you may remember from the Steve Jobs lesson. It is when the spreading starts, and where tumor spreads
to that determines the extent that a cancer will cause disease, not the size of the primary tumor
Cancers that have a high grade and that are at Stage III or Stage IV are the most difficult to treat, as we
shall see in Unit 5
But low grade and stage tumors present their own problems, since the appearance of the tumor itself is
not enough for us to predict when or even whether that tumor will become metastatic in the future. Hence
leaving a low-grade/stage tumor in place in the hope it will never metastasize can be a successful strategy
when a tumor is known to grow slowly, as prostate tumors do, but may cause problems when a tumors
mutates rapidly.
Wo r k b o o k
Lesson 4.1
MC Questions:
Tumors, cancer and disease: local and systemic symptoms
Even a benign tumor can cause local symptoms if it is large enough, but as it becomes malignant and
begins to metastasize it can cause symptoms well beyond the area in which the tumor first arose.
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5. True or False: Low grade and stage
cancers are usually nothing to worry
about.
aa. True.
bb. False.
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117
LESSON READINGS
DEFINITIONS OF TERMS
Cachexia – or wasting syndrome
is a loss of weight, muscle atrophy, fatigue, significant weakness
or significant loss of appetite in
someone who is not actively trying to lose weight.
Purely localized symptoms will initially entail:
MC Questions:
■■ Formation of a ‘lump’ (like the salivary gland tumor in
Figure 1) as the tumor starts to grow.
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Then as the tumor becomes malignant and invades the
stroma the symptoms might include:
■■ Pain where the ‘lump’ presses on nerves in the stroma.
■■ Bleeding (If the pressure of the ‘lump’ causes blood
vessels in the stroma to break).
If the tumor metastasizes, bleeding can become more
generalized and cause:
Figure 5: A colon tumor
(arrow) that has disrupted blood
vessels in the stroma to cause
bleeding. It may result in cachexia.
■■ Impaired blood flow to vital organs.
■■ Loss of energy when the bleeding is really excessive.
Bile ducts – tubes that move bile
from the liver to the intestine.
Bile – a fluid produced by the
liver that aids in the digestion of
lipids
The symptoms a tumor causes will depend on where the tumor first formed and where it has metastasized. Tumors from epithelial cells, which line tubes that run through the body will block the activity of that
area of the tube and if they grow large enough sometimes disrupt the function of the entire organ. For
example, tumors of the epithelia of the gastrointestinal tract such as the
stomach and colon are often associated with weight loss and a loss of
energy. This maybe because food processing itself has been blocked,
or because the presence of the tumor leads to a feeling of fullness
that causes decreased appetite. Together these symptoms lead to
Cachexia.
Jaundice – a yellow color of the
skin, mucus membranes or eyes
caused by bilirubin a byproduct of
old red blood cells that cannot be
broken down properly by the liver.
Wo r k b o o k
Lesson 4.1
Figure 6: Liver tumors
prevent old blood cells
being cleared, leading to
jaundice.
In the case of pancreatic cancer, weight loss observed is caused by
blockage of bile ducts, which are responsible for secreting bile, a fluid
important for digestion (you may remember bile as “yellow bile” from
Galen’s work). Blocking bile secretion prevents digestion and also leads
to anorexia.
Damage to the liver or gall bladder prevents them disposing of old
blood cells and leads to jaundice, a yellowing of the skin and mucous
membranes.
6. When is cachexia likely to be seen?
(Circle all correct.)
aa. In a large focal tumor.
bb. In a small focal tumor.
cc. In an extensive metastasis.
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118
LESSON READINGS
MC Questions:
Tumors of the lungs impair breathing, often leading to coughing. Unfortunately, coughing can be due to
many causes (such as inhaling toxic environmental chemicals such as cigarette smoke). Because of this
lung cancer is often difficult to diagnose.
Because the brain controls so many bodily functions tumors in the brain
can have many different effects on function and behavior. Symptoms are
usually caused by the pressure the growing tumor exerts in the closed
environment of the skull and may range from general headaches to very
specific symptoms that relate to where the tumor is located, such as:
■■ Double vision
7. Why is it often hard to diagnose lung
cancer at early stages?
aa. There are no good diagnostic
tools.
bb. Coughing symptoms are present
in cancer and in 'healthy' people.
cc. Lung cancer doctors are not
paid well.
dd. All are reasons.
■■ Trouble speaking
■■ Trouble moving
Symptoms are not even necessarily physical. Again depending on
where the tumor is located typical symptoms are emotional problems
and memory loss.
Figure 7: Brain
tumor (arrow) in an
area responsible for
impulse control and
social behavior.
One interesting case of a brain tumor’s unusual symptoms involved a man imprisoned on charges of
child molestation. Before his arrest he had been hospitalized with frequent severe headaches. Eventually,
his doctors discovered an egg-sized tumor in the part of his brain responsible for impulse control and
social behavior. After the doctors removed the tumor, his behavior returned to normal until the tumor
began to regrow, at which time he began to exhibit the antisocial behavior he had displayed before. While
behavioral disorders are not always related to brain tumors, tumors often cause unexpected symptoms.
Wo r k b o o k
Lesson 4.1
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8. Which of the following are NOT
disrupted by brain tumors?
aa. Memory.
bb. Behavior.
cc. Speech.
dd. All are disrupted.
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119
STUDENT RESPONSES
Describe the relationship between cancer grade/stage and disease. What distinguishes the type of symptoms caused by
benign tumors from those caused by malignant tumors?
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Wo r k b o o k
Lesson 4.1
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120
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.1
DEFINITION
Bile
A fluid produced by the liver that aids in the digestion of lipids.
Bile ducts
Tubes that move bile from the liver to the intestine.
Cachexia
Loss of weight, muscle atrophy, fatigue, significant weakness or significant loss of appetite in someone who
is not actively trying to lose weight.
Cancer grade
A classification system that characterizes cancer cells based upon how similar they look to their normal
counterparts.
Cancer stage
A classification system that describes the extent to which a tumor has spread.
Focal Tumor
A tumor that is localized to a specific part of an organ.
Hyperproliferation
The rapid growth of cells.
Jaundice
Yellow color of the skin, mucus membranes or eyes caused by bilirubin a byproduct of old red blood cells
that cannot be broken down properly by the liver.
Lymph nodes
Organs of the lymphatic system that collect and process lymph fluid from nearby organs.
Melanoma A malignant tumor of the skin that is often asymmetrical and multicolored.
Metastasis
The spread of malignant tumor cells to other parts of the body through blood/lymph vessels.
Mole
A focal tumor of the skin
121
LESSON 4.2 WORKBOOK
How can tumor cells leave home?
DEFINITIONS OF TERMS
Benign tumor – a tumor that is
hyper-proliferating, but has not
spread beyond the local area of
the epithelium where it originated
– not cancerous.
Malignant tumor – a hyperproliferating tumor that has acquired
the ability to migrate into the surrounding stroma - cancerous
Metastatic tumor– a hyperproliferating malignant tumor that
has acquired the ability to travel
through the blood and lymph to
secondary sites – cancerous.
Metastases – metastatic tumors.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.2
The difference between a benign tumor and a malignant tumor is the capacity to
migrate away from its initial site. This lesson focuses on how a focal tumor that
has developed the capacity to metastasize is able to break out of the basement
membrane surrounding the tissue, invade the stroma, and then travel through the
bloodstream or the lymph to the nearest lymph nodes.
Three steps to cancer: Proliferation, Invasion and metastasis
In the last lesson we defined the stages a normal epithelial cell goes through to become a cancer – first
forming a focal benign tumor that is hyper-proliferating but still localized in the epithelium, then transforming into a malignant tumor that is able to migrate out of the epithelium into the stroma, and finally traveling
through the bloodstream and lymph into secondary organs thereby becoming a metastatic tumor. Both
malignant and metastatic tumors are considered cancers because they cause symptoms that extend
beyond a limited area of the epithelium. It is important to remember that all these events are rare – few
normal cells form tumors, most tumors are not malignant and not all malignant tumors metastasize. A
key goal in cancer treatment is to be able predict which benign tumors will become malignant, and which
malignant tumors will metastasize. Sometimes the transition from benign to malignant tumor is easily
spotted - moles are a good example, but most often it is not because the tumor is internal. Nonetheless
tumors that remain at the primary site, whether benign or malignant, once detected, are often relatively
easy to treat either surgically or with drugs. As a result primary malignant tumors only cause about 10%
of all cancer deaths. The remaining 90% of cancer deaths occur because the malignant tumor has
metastasized to other sites within the body. Metastases are problematic for many reasons: First, a single
primary tumor may give rise to multiple metastases: In this case surgical removal may be impractical.
Second metastases are often resistant to the drugs used to treat the primary tumor: In this case they may
be impossible to treat. Finally metastases can occur relatively early in cancer development and remain
undetected until they produce systemic symptoms – a lingering cough for example – that are difficult to pin
down. At that point surgery may be impractical and drug treatment impossible (Steve Jobs is an example
of this). But how does a benign tumor become malignant and then metastatic?
MC Questions:
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1. Which of the following are most
likely to cause death from cancer?
aa. Focal benign tumor.
bb. Focal malignant tumor.
cc. Metastatic tumor.
dd. All are equally likely to cause
death.
2. Which of the following differentiates
a metastatic cancer cell from a
malignant cancer cell?
aa. Hyperproliferative growth.
bb. Ability to enter blood.
cc. Ability to enter the stroma.
dd. All of the above.
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LESSON READINGS
Figure 1 shows the 3 steps of cancer
development:
MC Questions:
■■ STEP 1: Focal proliferation
3. Which of the following provides
a selective pressure? (Circle all
correct.)
aa. Taking antibiotic.
bb. High number of tumor cells in a
tissue.
cc. Lack of blood vessels in tissue.
dd. The ability to fly.
■■ STEP 2: Invasion
■■ STEP 3: Metastasis
DEFINITIONS OF TERMS
Invasion – the process of tumor
cells passing from the epithelium
into the stroma.
Selective pressures – conditions in the environment that favor
the growth of cells with certain
characteristics.
Basement membrane – a thin
fibrous layer of proteins below
the epithelial cells that acts as
a fence or anchor, keeping the
epithelial cells in place.
Stroma – fibrous proteins and
cells below the basement membrane that support the epithelium.
Endothelial cells – cells that line
blood/lymph vessels.
The principle underlying the transitions
between steps 1 – 3 is the same: Selective
pressure. As the benign tumor in Step
1 gets bigger oxygen will be increasingly
scarce, so cells that have acquired
mutations enabling them to migrate
away from the tumor mass will have an
advantage. Likewise mutations that enable
cells to invade the stroma (shown in blue in
the picture) closer to capillaries will also be
Figure 1: The three steps a normal cell
an advantage, as will mutations that enable
undergoes to become a metastatic cancer cell.
malignant cells to invade the capillaries and
Only cells in steps 2 and 3 are cancerous. Each
step occurs rarely.
travel to distant sites. Figure 1 also defines
the three barriers a tumor cells has to break
through: the basement membrane, a thin
fibrous layer of proteins that fences off the epithelium and anchors the cells so they remain in the correct
orientation in the tubes they make in the body; the stroma, the fibrous proteins and cells that provides
support to the epithelium as a whole; and the endothelial cells that must be breached for the tumor to
enter either the bloodstream or the lymphatics. Clearly not all big benign tumors experience this selective
pressure (think of the salivary tumor), and not all small tumors stay benign (think of the mole) but selective
pressure is nonetheless an important biological principle that dictates which mutations drive development
and which do not.
From benign to malignant: Tumor invasion
Wo r k b o o k
Lesson 4.2
The first step a benign tumor takes in becoming malignant involves breaking out of the basement
membrane ‘fence’ around the epithelium. This requires the tumor cells to acquire two new properties; the
ability to move and the ability to break down the basement membrane itself. Epithelial cells don’t normally
move – they are tightly attached to their neighbors, and as we learned before, this contact provides
signals that prevent them proliferating unnecessarily. But as we have also learned before, tumor cells are
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4. Which of the following is a reason
tumor cells might evolve to become
metastatic? (Circle all correct.)
aa. Lack of nutrients.
bb. Tumor is large.
cc. Blood vessels growing around
tumor.
dd. Tumor is old.
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LESSON READINGS
no longer tightly attached to each other and are no longer sensitive to these contact signals, which is why
they proliferate. Some tumor cells may develop further mutations that make them even less like normal
epithelial cells and more like motile cells, such as fibroblasts. These motile cells need just one further
change in order to become malignant – they need to be able to break down the tough fibers of the basement membrane and also, once they get there, the stroma.
DEFINITIONS OF TERMS
Motile – able to move.
Extracellular matrix – the
fibrous proteins in the stroma.
Proteases – enzymes that chew
up proteins into peptides and
amino acids. Are used by cancer
cells to degrade the fibrous proteins of the basement membrane
and stroma, allowing cancer cells
to invade the stroma.
Both the basement membrane and
the stroma can provide strength and
structure to the epithelium because they
are composed of tough fibrous proteins
(another name for these proteins is the
extracellular matrix). To break through
either the tumor cells need to cut these
tough fibers up. Cells cut up proteins
regularly using enzymes called proteFigure 2: Cancer cells secrete proteases that
allow tumor cells to invade the stroma and approach
ases, which can snip large proteins
the capillaries.
into peptides and then amino acids, as
the cell needs to refresh the proteins it
is made from. However, because the
basement membrane and stroma are both on the outside of cells the motile tumor cell needs not only to
make the right proteases but also to secrete them. Once the proteases are in contact with the basement
membrane or stroma they act like a lawn mower clearing a path for the tumor cells to travel through so
they can get closer to the oxygen they require.
A tumor cell that has made its way into the stroma it is considered malignant, and therefore cancerous.
One final set of mutations will transform the malignant tumor into a metastatic tumor. This transformation
entails passing between the endothelial cells that surround the capillaries and lymph vessels.
From malignant to metastatic: Lessons from wound healing
Wo r k b o o k
Lesson 4.2
Malignant tumor cells gain access to blood and lymph by exploiting processes normally used in wound
healing. Unlike the stroma, which is composed of fibrous proteins, blood and lymph vessels are
surrounded by endothelial cells that prevent them leaking. Clearly cutting the endothelial cells up with
proteases is not a solution. As we know, when a wound occurs, immune cells enter the damaged site
to prevent infection. The immune cells not only secrete proteases to break down the stroma so they
can move into the wound, they also secrete proteins called growth factors. These growth factors, called
vascular endothelial growth factors (VEGFs), stimulate growth of new capillaries, a process called
angiogenesis. These new capillaries in turn provide the nutrients necessary for the new cell growth at
the site of the wound.
MC Questions:
5. True or false: Tumor cells need to be
able to pass into the blood vessels in
order to become malignant.
aa. True.
bb. False.
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from invading stromal tissue? (Circle
all correct.)
aa. Proteases.
bb. Basement membrane.
cc. Endothelial cells.
dd. Lack of ability to move.
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LESSON READINGS
So VEGFs have two advantages for tumor cells – first
the new blood vessels they stimulate can provide the
tumor cells with the extra nutrients they will need as
they are proliferating. Second these new capillaries
are somewhat more leaky than their mature counterparts, allowing the tumor cells to crawl inside. Once
inside the blood (or lymph) vessels they are passively
transported to different sites.
DEFINITIONS OF TERMS
Vascular endothelial growth
factors (VEGFs) – secreted
proteins that signal to endothelial cells to grow which leads
to growth of new blood/lymph
vessels.
Angiogenesis – the process
of growing new blood/lymph
vessels.
Wo r k b o o k
Lesson 4.2
Clearly in a world of inadequate nutrients the ability to
secrete VEGF provides cancer cells with an enormous
selective advantage, and many tumor cells acquire
Figure 3: A wound stimulates
the ability to secrete VEGFs even before they are able
growth of new blood vessels that
to break through the basement membrane. However
provide nutrients to support cell
this VEGF cannot stimulate angiogenesis until the
proliferation to heal the wound.
tumor cells can secrete proteases to chew up the
stroma, allowing the VEGF access to the endothelial
cells. Hence the tumor cells are primed for angiogenesis as soon as they break out of the basement
membrane.
Once cancer cells are in the stroma they are under
significant selective pressure to escape. As we will
see, the very immune cells that efficiently prevent
infection after a wound can also deal with 99% of
cancer cells. Cancer cells that are able to metastasize therefore have the selective advantage of being
able to avoid immune cells .
The concept of selective pressure explains how
an environment where nutrients are limited can
Figure 4: Cancer cells secrete
favor cancer cells that can invade the stroma (by
VEGFs that promote growth of blood
secreting proteases) and stimulate angiogenesis
vessels surrounding a tumor.
(by secreting VEGF). Clearly, the more limited the
nutrients the stronger the pressure. Conversely,
tumors in tissues in which nutrients are plentiful because the tissue is well supplied with blood vessels
(highly vascularized) will experience less selective pressure, and tumors with those mutations will not
have an advantage. Hence these tumors metastasize less frequently than tumors in tissues with less
MC Questions:
7. How is wound healing like cancer
metastasis? (Circle all correct.)
aa. Stromal tissue is broken down
by proteases.
bb. Immune cells kill bacteria.
cc. New blood vessels are grown.
dd. A clot is formed.
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8. Which of the following is a reason
cancer cells promote angiogenesis?
(Circle all correct.)
aa. Cancer cells need nutrients.
bb. Cancer cells need more
proteases.
cc. Cancer cells need to enter blood.
dd. Cancer cells cause bleeding.
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LESSON READINGS
vasculature. This is less counterintuitive than it may
seem – remember that mature capillaries are less
leaky than new ones. Hence merely having a lot of
capillaries is not the same as having capillaries that
are accessible to the tumor.
DEFINITIONS OF TERMS
Vasculature – the blood vessels
in a given tissue.
Highly vascularized - many
blood vessels.
Wo r k b o o k
Lesson 4.2
We can sometimes accidentally promote tumor
spread by trying to remove a tumor surgically. As
wound that results heals, it will stimulate angiogenesis. The new blood vessels produced may allow
cells from the tumor remnants to escape from the
surgery site. An example of this was seen recently:
Fibroids are common benign tumors of the uterus
that can be uncomfortable and hinder fertility. SurgiFigure 5: A picture of a tumor
implanted below mouse skin. Over
cal removal through the abdomen is very invasive so
time more blood vessels form at the
a method was devised to insert a tiny probe (like a
site of the tumor.
stick blender) in through a small incision to break up
the tumors, which could then be sucked out easily.
Unfortunately some of the benign tumors had areas
of malignancy and if they remained they could persist and even metastasize. This method, while less invasive, is now discouraged because we cannot know which fibroids are wholly benign and which are not.
MC Questions:
9. Which of the following reasons
explains why tissues with high
vasculature have fewer metastatic
tumors than tissues with low
vasculature? (Circle all correct.)
aa. Tissues with high vasculature
have more immune cells.
bb. There is no selective pressure to
spread.
cc. Tissues with high vasculature
contain cells that are naturally
less metastatic.
dd. All of the above.
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STUDENT RESPONSES
Describe the pressures that drive a cancer cell to spread, and what pressures prevent cancer cells from spreading.
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Wo r k b o o k
Lesson 4.2
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.2
DEFINITION
Angiogenesis
The process of growing new blood/lymph vessels..
Basement membrane
A thin fibrous layer of proteins below the epithelial cells that acts as a fence or anchor, keeping the epithelial
cells in place.
Benign tumor
A tumor that is hyper-proliferating, but has not spread beyond the local area of the epithelium where it
originated – not cancerous
Endothelial cells
Cells like epithelial cells that line blood/lymph vessels.
Extracellular matrix
The fibrous proteins in the stroma.
Invasion
The process of tumor cells passing from the epithelium into the stroma.
Malignant tumor
Hyperproliferating tumor that has acquired the ability to migrate into the surrounding stroma - cancerous
Metastatic tumor
A hyperproliferating malignant tumor that has acquired the ability to travel through the blood and lymph to
secondary sites – cancerous. .
Metastases
Metastatic tumors.
Motile
Able to move.
Proteases
Enzymes that chew up proteins into peptides and amino acids. Are used by cancer cells to degrade the
fibrous proteins of the basement membrane and stroma, allowing cancer cells to invade the stroma.
Sarcoma
A cancer of stromal cells.
Selective pressures
Conditions in the environment that favor the growth of cells with certain characteristics.
Stroma
Fibrous proteins and cells below the basement membrane that support the epithelium.
Vascular endothelial
growth factors (VEGFs)
Secreted proteins that signal to endothelial cells to grow which leads to growth of new blood/lymph vessels.
Vasculature
The blood vessels in a given tissue.
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LESSON 4.3 WORKBOOK
How do tumor cells find a new
home?
DEFINITIONS OF TERMS
Colonization – the process of a
metastatic cancer cell entering
and forming a tumor in a new
organ.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.3
Only 10% of cancer deaths are caused by primary tumors, the remaining 90%
are caused by metastatic tumors that have settled in secondary sites. This lesson
focuses on what makes a secondary site attractive to a particular cancer cell. The
‘seed and soil’ hypothesis that each metastasis has specific requirements that only
certain organs can provide. Understanding what those requirements are is important because metastatic tumors are usually much harder to treat than primary
tumors.
Colonization: metastatic cancer cells settle in a secondary site
As you may remember from
Unit 1, Galen proposed that
cancer is caused by an
accumulation of ‘black bile’.
Black bile was never isolated,
but metastatic cancer cells that
travel round blood stream, like
a ‘liquid cancer’ are not unlike
black bile. However, unlike
Galen’s version metastatic
cells will not survive unless
Figure 1: Steps of metastasis include invasion of
they acquire the traits that
surrounding tissue, entering blood or lymph, transport
through circulation, and colonization in another organ.
enable them to exit the
blood vessels and settle in a
secondary site, a process that
is called ‘colonization’. We have talked about the selective pressures on cells that favor a particular set
of mutations. In the case of colonization the selective pressure comes from the physical forces of blood
traveling around the bloodstream that can otherwise destroy the metastatic cells.
MC Questions:
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1. Which of the following is a step in
the process of metastasis? (Circle all
correct.)
aa. Entering blood stream.
bb. Killing red blood cells.
cc. Exiting blood stream.
dd. Forming tumor in second organ.
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LESSON READINGS
Benign epithelial tumors become malignant by acquiring mutations that allow them to become motile and
invade the stroma. By the time metastatic cells enter the blood stream, they have ceased to behave like
the normal epithelial cells they once were. Nevertheless, if they are to colonize secondary sites successfully, some of these behavior changes need to be undone – motility is a good example. Metastasized
cells that stay motile may never be able to settle in a secondary organ and may persist in the blood
stream or lymph indefinitely. But simply losing the ability to migrate is not sufficient to permit successful
colonization. The secondary organ must have specific characteristics – that are often very different from
the primary site – for instance cancers whose primary tumors are in breast often prefer to settle in bone,
while primary colon cancers prefer to settle in liver.
DEFINITIONS OF TERMS
How cancer cells select secondary sites
‘Seed and fertile soil’ hypothesis – a theory by Stephen Paget
that proposed that secondary
tumors only form when they are
in the appropriate environment for
their growth.
We learned in Unit 1 how Stephen Paget proposed
that metastatic cancer cells behave like ‘seeds’ that will
only settle down and flourish when they find ‘fertile soil’.
Paget’s ‘seed and fertile soil’ hypothesis stated that
an organ would act as ‘fertile soil’ if:
■■ The metastatic cells pass through that organ
frequently.
■■ The metastatic cell can grow in that organ easily.
Portal vein – a major blood vessel that takes blood from the GI
tract through the liver and back to
the heart.
Wo r k b o o k
Lesson 4.3
Cancer cells can reduce the amount of time they spend
in the bloodstream by colonizing nearby organs and
take advantage of the fact that the circulatory system is
Figure 2: Colon cancers enter
organized to link certain organs together. For instance,
the blood stream at the portal vein,
which first passes through the liver
the portal vein is a major blood vessel that links the
then to the heart. Many colon canGI tract to the heart. Hence metastatic cancers of the
cers form secondary tumors in the
colon are likely to form in the liver because the blood
liver.
supply from the colon passes through on its way back
to the heart. Metastatic breast cancer cells colonize the
lungs for a similar reason. On the other hand the brain is not linked to other organs in the same way and
therefore cancer cells do not colonize it because of proximity.
However organs are not just passive ‘fertile soils’ that cancer cell ‘seeds’ land on and grow in. If that were
the case the brain would never be the site of secondary tumors, whereas it often is. In fact a study that
investigated where human cancers metastasized to revealed that only 66% of cancer metastases could
MC Questions:
2. Which of the following determines
the ability of an organ to form
secondary tumors?
aa. The environment of the organ;
bb. The closeness to the organ with
a primary tumor;
cc. Is the organ accessible by blood;
dd. All of the above.
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LESSON READINGS
be accounted for by their proximity to the
primary tumor via the circulatory system.
The remaining 30% of metastases
seemed to depend on the environment
of the secondary organ that made it
particularly attractive to the metastasizing
cells.
DEFINITIONS OF TERMS
Chemokines – proteins secreted by cells that attract or repel
cells to a certain site.
Serotonin – a neurotransmitter
that also serves as a chemokine
for some cancer cells.
Many organs actively attract cancer
cells to grow in them by releasing protein
factors, called chemokines. If the
Figure 3: Serotonin is secreted by bone cells
cancer cells express receptors for those
(osteoblasts and osteocytes) to attract tumor cells
chemokines they will home in towards the
to enter bone tissue.
source of the chemokines, In fact 20% of
all metastases form because of attractive
chemokines. Other chemokines can actively repel cancer cells from an organ site. The remaining 14% of
all metastases form in organs because repellent chemokines shut them out of other sites. One example of
an attractive chemokine is the neurotransmitter serotonin that is present both in brain tissue, as we might
expect, but also in bone tissue. Serotonin acts as a chemokine for metastatic breast cancer cells and as a
result breast cancer commonly colonize both bone and brain, even though neither organ is directly linked
to the breast through the circulatory system.
MC Questions:
3. True or False: The types of mutations
a cancer cell develops over time
determines what organs it is capable
of colonizing.
aa. True.
bb. False.
4. How do chemokines attract or repel
cells from a specific site in the body?
aa. They activate neurons to
promote cell movement to site.
bb. They bind receptor on cells and
promote movement to or away
from site.
cc. They degrade stroma to increase
cell movement.
dd. All of the above.
The major organ sites for metastasis
Four organs develop more secondary tumors than any other sites. These are liver, lungs, brain and bone.
As we discussed before, liver and lungs are linked to many organs via the circulation, whereas brain
and bone secrete attractive cytokines such as serotonin. Secondary tumors in these organs are usually
detected via the symptoms they produce, as we saw in Lesson 1. For example:
■■ Secondary tumors in the liver cause pain, jaundice, malnutrition and cachexia.
■■ Secondary tumors in the lung cause pain , coughing, difficulty breathing and pneumonia.
■■ Secondary tumors in the brain cause headache, blurred vision, memory loss, behavior change and
coma.
Wo r k b o o k
Lesson 4.3
5. What are the most important factors
that determines ability of cancer
cells to form secondary tumors?
aa. Environment compatibility.
bb. Secretion of chemokines.
cc. Closeness to organ of primary
tumor.
dd. All of the above.
■■ Secondary tumors in bones cause pain, fractures, paralysis and anemia if bone marrow is affected.
131
LESSON READINGS
DEFINITIONS OF TERMS
Melanomas – Malignant cancers
of the skin
Melatonin – the black pigment
in skin
Wo r k b o o k
Lesson 4.3
Figure 4: Tumors in primary organs such as
prostate, pancreas, breast, or colon prefer to form
secondary tumors in certain organs (preference is
shown by arrow thickness).
MC Questions:
There is still a lot we do not understand
about how tumors form and metastasize. Not all organs form primary
tumors, and not all organs form
secondary tumors. For instance, while
brain and bone cancers are quite rare,
secondary tumors in the brain and
locations for secondary tumors. We
particularly do not understand all the
attractive and repellent chemokines
involved in making a specific organ into
‘fertile soil’. Answers to these questions
will be important as we try to develop
treatments for metastatic tumors.
Remember, 90% of all deaths from
cancer occur because of metastases.
One challenge with diagnosing a tumor is to determine whether if is a primary tumor or a metastasis.
It may be unclear if that tumor is a primary tumor or a secondary tumor. It turns out that even though a
primary tumor loses many of the characteristics
of the normal cell from which it originates, it often
retains certain distinguishing features. For example
melanomas that form on the skin are often
pigmented with the black pigment melanin. Even
after the primary tumor has become malignant,
then metastatic and finally colonized a secondary
site (typically the lymph node, at least at first) the
cancer will retain the melanin, which can then
be used for diagnosis. Typically, ‘lung cancer’ or
‘breast cancer’ refers to the primary site of the
Figure 5: Primary tumor of lymph
tumor. In contrast a secondary tumor is referred to
node is composed of lymph cells, while
as ‘secondary lung cancer in the liver’ or ‘seconda secondary tumor (arrow) of lymph
ary breast cancer in the bone’. These are critical
node contains mostly melanoma cells,
distinctions because primary and secondary
and looks like a melanoma, rather than
a lymph tumor.
tumors respond very differently to drugs, as we
shall see.
6. Which organ is a primary prostate
cancer most likely to colonize?
aa. Liver;
bb. Lung;
cc. Brain;
dd. Bone.
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7. True or False? A secondary
tumor resembles the organ it has
colonized more than the organ it first
developed in.
aa. True.
bb. False.
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LESSON READINGS
Taking a step back, the changes that a normal cell must undergo to end up colonizing a secondary organ
are quite impressive. The cell has to acquire random genetic mutations that enable it to:
■■ Hyperproliferate by failing to respond to external signals that stop growth.
■■ Avoid apoptosis even though the DNA might be very abnormal.
■■ Become motile.
■■ Secrete proteases that enable it to break through the basement membrane and migrate through the
stroma.
■■ Secrete VEGFs that induce new blood vessels to form and sneak into the blood vessels through the
endothelium.
■■ Survive the physical forces in the bloodstream and lymph.
■■ Sneak back out of the endothelium.
■■ Identify and respond to cytokines in specific organs.
■■ Lose the ability to migrate and settle down.
Given that all these characteristics have to appear in the right place at the right time, while occurring
randomly it is not surprising that so few cells become cancerous and even fewer metastasize. It is also not
surprising that the likelihood of cancer increases with age as the opportunity for all these changes to occur
also increases. However it is not just statistics that protects us from developing cancer, in the next lesson
we will learn about the critically important role the immune system plays in protecting against cancer.
Wo r k b o o k
Lesson 4.3
Notes:
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133
STUDENT RESPONSES
Describe the process by which a metastatic cancer cell 'chooses' to enter a secondary organ, explaining why most secondary
cancers are close to the organs of the primary tumor.
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Wo r k b o o k
Lesson 4.3
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134
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.3
DEFINITION
Chemokines
Proteins secreted by cells that attract or repel cells to a certain site.
Colonization
The process of a metastatic cancer cell entering and forming a tumor in a new organ.
Melanoma
Malignant cancer of the skin
Melatonin
Black pigment found in skin
Portal vein A major blood vessel that takes blood from the GI tract through the liver and back to the heart.
Primary tumor
The original focal tumor that a cancer originated from.
Secondary tumor
A tumor formed by a metastatic cancer cell in a site distinct from the original focal tumor.
‘Seed and fertile soil
hypothesis’
A theory by Stephen Paget that proposed that tumors only form when they are in the appropriate environment for their growth.
Serotonin
A neurotransmitter that also serves as a chemokine for some cancer cells.
135
LESSON 4.4 WORKBOOK
Why don’t we all die from cancer?
Cancer is a rare event thanks to the activity
of the immune system, which is able to
eliminate more than 99% of all tumor cells.
This lesson will explain how the immune
system normally controls cancer cell growth
and metastases, and how in rare instances
cancer cells can actively subvert the immune
system and escape immune surveillance.
How does the immune system identify cancer cells?
The role of the immune system in preventing cancer is rarely discussed, but in fact the immune system
takes care of over 99% of tumor cells, killing them before they can become malignant. It is very rare that
a mutated cell is able to escape immune surveillance. You may remember from the Infectious Diseases
module that the immune system is tasked with protecting the body against foreign agents, such as pathogens and that the immune system is able to recognizes these pathogens as foreign because they express
antigens on their surface that immune cells detect as ‘non-self’. But cancer cells are different from foreign
pathogens in that they come from the host itself. What characteristics do they have that allows the immune
system to categorize them as ‘non-self’?
Wo r k b o o k
Lesson 4.4
As we well know, cancer cells are typically heavily mutated or express proteins not found in normal cells ­—
for example mature cells usually don't’ express the enzyme telomerase which prevents cells aging, while
cancer cells do. Similarly cancer cells revert to a less differentiated state to help them migrate in the stroma
and enter the bloodstream ­— this too is out of context. As the cancer cells acquires more mutations or
expresses more out-of-context proteins the odds of it being detected as ‘non-self’ increase.
MC Questions:
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1. True or False: Cancer cells express
mostly the same proteins as normal
cells, which is why the immune
system cannot detect them easily.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
MHC class I proteins (MHC
I) – proteins that present short
peptides of proteins made in a
cell on the surface of the cell to be
recognized by the immune system.
Immunosurveillance – the
principle that the immune system
is responsible for identifying and
killing cancer cells.
Innate immunity – the non-specific arm of immune system that
includes physical barriers, mucus
membranes, and NK cells.
The immune system detects cells as ‘self’ or ‘non-self’ by examining the small fragments of proteins
cells regularly present on their surface. When cells degrade their proteins with proteases, MHC class I
proteins (MHC is short for major histocompatibility complex) deliver these protein fragments to the cell
surface and present them on the outside world. Immune cells survey these protein fragments and, based
on their structure, decide whether they are ‘self’ or ‘non-self’. For example if a cell is infected with a virus
and makes viral proteins as a result, some of these viral proteins will be degraded and then presented
to the outside by the MHC. Passing immune cells will survey the virus protein fragments, determine that
they are ‘non-self’ and direct the virus-infected cell to be killed. The same is true for tumor cells, except
they aren’t infected. Instead MHC proteins present fragments of mutated or out-of context proteins on the
cell surface for immune cells to decide that they are ‘non-self’ and direct the cells to be killed. This kind of
immune system activity against cancer is called immunosurveillance.
Killing cancer cells
You may also remember that the two main branches of the immune system – innate and adaptive
immunity – play different roles. Innate immunity includes physical barriers such as the skin, and mucus
membranes that trap pathogens like bacteria that are trying to penetrate into the body. The innate
immune system located in these barriers contains cells that are able to kill anything they do not recognize, using a ‘shoot first, ask questions later’ approach to handling pathogens. In contrast a major role of
the adaptive immune system is to remember previous infections so that the body is prepared to handle
Adaptive immunity – the specific
arm of immune system recognizes
pathogens and mounts responses
based out of previous exposure.
Includes B and T cells.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.4
Figure 1: Antibodies that recognize 'non-self' proteins expressed on the
surface of cancer cells will bind cancer cells. These antibodies are bound
by NK cells, which are then activated and lyse the target cell by triggering
apoptosis.
similar pathogen threats in the future. The adaptive immune system is composed of two major types of
cells: B cells make antibodies and are most useful for dealing with external pathogens like bacteria, and T
cells that are most useful for handling internal pathogens like viruses.
MC Questions:
2. Where do the peptides that MHC I
proteins bind mostly come from?
(Circle all correct.)
aa. Proteins that are outside the cell.
bb. Proteins from pathogens.
cc. Proteins made within the cell.
dd. Signaling molecules.
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3. True or False: Mucus membranes
play an important role in preventing
cancer spread.
aa. True.
bb. False.
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DEFINITIONS OF TERMS
Natural Killer (NK) cell – an
innate immune cell that binds to
antibodies to kill cells, or kills cells
that lack MHC I on the surface.
Cytotoxic T lymphocyte (CTLs)
– a type of T cell that is responsible for killing cells that express
non-self peptides bound to MHC I
on their surface.
Antibodies are chiefly present in mucus
and the bloodstream so they only play a
role in killing tumor cells found in these
areas. Antibodies recognize the cancer
cells and then use natural killer (NK)
cells to kill them. When an antibody
recognizes a specific antigen on a cell, it
attaches to it with its ‘arms’ leaving the tail
of the antibody - its so-called Fc portion
- protruding into space (see Figure 2). A
passing NK cell can interact with the Fc tail
of the antibody via its own Fc receptors.
The binding of the Fc receptors to the Fc
tail of the antibody, which itself is bound to
antigens on the cell surface activates the
NK cells so that they can tell the cancer cell
to initiate apoptosis.
Clonal expansion – the growth
of adaptive immune cells in
response to detection of a pathogen or cancer cell.
Figure 3: When NK cells detect
MHC on the surface of the cell, that
signals to inhibit NK cell killing activity.
When there is no MHC, NK cells are
active to kill the cell.
Wo r k b o o k
Lesson 4.4
MC Questions:
4. Which of the following is a way for
cancer cells to evade the immune
system? (Circle all correct.)
aa. Stop expressing MHC I.
bb. Surround themselves with other
cells.
cc. Trigger necrosis.
dd. Stop expressing oncogenes.
Figure 2: A cancer cell expressing a “nonself” peptide will bind a CTL, which will cause
replication of that CTL, called clonal expansion.
An increase in number of CTLs will allow for
immune killing of that tumor.
It is important to note that while the antibody interaction with the protein antigen because cancer cells
present protein fragments on their surface with MHC
like virus infected cells do, they are also targets of the
adaptive immune system, like virus infected cells are.
When the immune system surveys a cell infected with
a virus and decides it is ‘non-self’ it sends a cyotoxic
T cell (CTL) to kill it. CTLs resemble antibodies in
that they only recognize one kind of protein fragment presented by the MHC, just like each antibody
recognizes only one antigen. When a CTL identifies a
single ‘non-self’ protein fragment from the cancer cell it
also kills the cancer cell by inducing apoptosis, just like
the NK cell does.
Finally once an antibody has interacted with its antigen the B cell makes more antibodies (this is called
clonal expansion). In just the same way, once a CTL has recognized a tumor protein fragment on the cell
surface numbers also increase rapidly through clonal expansion. In this way CTLs can also cause many
cells in a tumor to die.
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5. 5. True or False: Immunoevasion is
an evolved trait developed in cancer
cells by random mutation.
aa. True.
bb. False.
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MC Questions:
How cancer cells can escape the immune system
Given that all dividing cells accumulate mutations randomly it should not be surprising that cancer cells,
which are dividing more rapidly than most, may eventually acquire random mutations that will allow them
to avoid immune surveillance and escape immune system control. This is called immunoevasion. We
can identify three different categories of mutation that play these roles:
■■ Mutations that allow the cancer cell to hide its identity so it is no • longer recognized as ‘non-self’.
DEFINITIONS OF TERMS
■■ Mutations that allow the cancer cell to avoid the ‘die’ signal.
■■ Mutations that actually kill the immune cells.
Immunoevasion – the process
by which cancer cells attempt
to avoid immune detection and
attack.
CTL cells recognize cancer cells as ‘non-self’ because of the protein fragments they present on their
surface in conjunction with MHCI. These fragments may come from out-of-context proteins or mutated
proteins. Both can be reversed, but maybe at some cost to the tumor cell: For example we mentioned
tumor cells that are detected as ‘non-self’ because they produce telomerase out of context. Telomerase
repairs telomeres so the tumor cell does not age normally. Hence a tumor cell that no longer expresses
telomerase out-of-context will no longer be detected as non-self and therefore will not be targeted for
killing by the immune system. Unfortunately this does not mean it won’t die - it now may very well die due
to regular aging!
Tumors cells can take another tack to hide their identity: In
order to recognize protein fragments CTL cells need the
MHCI to present them properly on the tumor cell surface.
Cancer cells that no longer express MHCI can’t present the
fragments properly, so CTL cells won’t be able to detect
and kill them.
Wo r k b o o k
Lesson 4.4
The immune system uses NK cells to outsmart tumor cells
that no longer express MHCI. Unlike CTL cells, NK cells
use antibodies not MHCI to recognize surface protein. If
an antibody has bound to the ‘non-self’ fragment an NK cell
can swoop in and kill the tumor cell even though CTLs no
longer can.
Figure 5: Cancer cell
(brown) surrounds itself
with platelets (blue) to avoid
recognition in the blood stream
by NK cells.
6. Which of the following is a negative
effect for the cancer cell that is
attempting to evade the immune
system? (Circle all correct.)
aa. Decreased gene expression
leads to platelet binding.
bb. Decreasing oncogene
expression prevents growth/
survival of cancer cell.
cc. Evasion leads to more spreading
and less growth.
dd. Decreasing MHC I expression
makes cell sensitive to NK cell
attack.
7. Why do cancer cells not die when
exposed to death ligands?
aa. Membrane is resistant to
ligands.
bb. Apoptosis pathway in cells is
shut down.
cc. They make their own death
ligand.
dd. All of the above.
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But cancer cells fight back! Most NK cells are found in blood and lymph, and tumor cells in the blood can
evade NK cells by surrounding themselves with platelets. Platelets are normally responsible for clotting
wounds, and large numbers are found in the blood. Tumor cells can surround themselves with a platelet
‘shield’ that guards against NK cells recognizing and attacking them.
DEFINITIONS OF TERMS
Platelets – a type of blood cell
responsible for clotting that is
present in very high numbers in
the blood stream, and can bind
to cancer cells to allow them to
evade the immune system.
Immune cells kill infected cells, and tumor cells by secreting signals known as death ligands which
interact with death receptors on the cells in question. Binding of the death ligand to the death receptor
activates the apoptosis pathway and the cell effectively commits suicide. This is normally an extremely
effective way to kill a damaged or infected cell. Unfortunately, as we well know, one of the earliest mutations that tumor cells acquire are mutations that inactivate the apoptotsis pathway by making it insensitive
to death signals and in this way promoting growth and survival. Tumors that have already acquired mutations in the apoptosis pathways will not be sensitive to immune killing, which is therefore most effective in
early stage tumors.
To make matters worse, tumor cells that are resistant to apoptosis sometimes flip the script on immune
control by synthesizing and releasing their own death ligands. These death ligands will be able to kill
nearby immune cells that have an active apoptosis pathway. If a CTL or NK cell attaches to a tumor cell
that is secreting death ligands it will be activated to apoptose.
Nonetheless the immune system can take care of a vast number of potentially problematic tumor cells
provided they are still able to apoptose. The tumors left are those able to subvert immune control and
become detectable.
Wo r k b o o k
Lesson 4.4
Notes:
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STUDENT RESPONSES
Immunotherapy is a recently developed strategy to treat cancers by boosting the body’s immune system. Can you give twothree examples of how the immune system could be improved to kill cancer cells?
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Wo r k b o o k
Lesson 4.4
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.4
DEFINITION
Adaptive immunity
The specific arm of immune system recognizes pathogens and mounts responses based out of previous
exposure. Includes B and T cells.
Clonal expansion
The growth of adaptive immune cells in response to detection of a pathogen or cancer cell.
Cytotoxic T lymphocyte
(CTLs)
A type of T cell that is responsible for killing cells that express non-self peptides bound to MHC I on their
surface.
Immunoevasion
The process by which cancer cells attempt to avoid immune detection and attack.
Immunosurveillance
The principle that the immune system is responsible for identifying and killing cancer cells.
Innate immunity
The non-specific arm of immune system that includes physical barriers, mucus membranes, and NK cells.
MHC class I proteins
(MHC I)
Proteins that present short peptides of proteins made in a cell on the surface of the cell to be recognized by
the immune system.
Natural Killer (NK) cell
An innate immune cell that binds to antibodies to kill cells, or kills cells that lack MHC I on the surface.
Platelets A type of blood cell responsible for clotting that is present in very high numbers in the blood stream, and can
bind to cancer cells to allow them to evade the immune system.
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Unit 5:
Unit 5: Introduction
Where are we heading?
Unit 1: What is cancer and why should we care?
Unit 2: What does it mean to be a 'normal' cell?
Unit 3: How do normal cells become cancerous?
Unit 4: How does cancer make us sick?
Unit 5: How do we treat cancer?
______________________________________
In Unit 5 we'll look at how we diagnose and treat
cancer and the challenges and opportunities for
designing better screens and treatments in the
future.
Lesson 5.1 will explore the difference ways in which tumors can be
detected. Lesson 5.2 grapples with the limitations of these screens
and what they can and can't tell us. Lesson 5.3 investigates the
different methods of treating cancer that are commonly available and
allows you to discuss their strengths and weaknesses. Lesson 5.4
follows the patients you studied in the previous lesson to investigate
how effective cancer treatments really are, and what other options
for care exist. Lesson 5.5 brings us into the 21st century - what would
an effective treatment for cancer look like and how close are we to
having one? Lesson 5.6 takes a big step back to review the whole
module. The war on cancer has cost us nearly $100 billion dollars
over 50 years. What were the challenges, could they have been
foreseen? Did we get our money's worth? You decide!
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LESSON 5.1 WORKBOOK
How do I know if I have cancer?
In the previous 4 units we have learned about how cancer occurs its pathology of
cancer. But no investigation of cancer will be complete without an understanding of
how it is diagnosed and treated. It will not be surprising that cancer is best treated
when it is detected early, but every detection method has strengths and weaknesses.
In this lesson we will begin to explore the methods used to diagnose cancer, and
their strengths and weaknesses.
Detecting and diagnosing cancer: Self examination
In the last several units we have learned that 90% of deaths from cancer are due to metastasis. Clearly we
need to identify a cancer before metastasis occurs. But we have also learned that metastasis can occur
very early after a primary tumor becomes malignant. Clearly we also need to be able to identify which
primary tumors a likely to become malignant. These two critical problems in tumor detection —‘Which
tumors will become malignant?’ and ‘When will a malignant cancer metastasize?’ — must be solved if we
are to treat cancer effectively. Unfortunately each tumor behaves very individualistically: A tumor acquires
mutations randomly, so while we can define the route a tumor must take to become malignant, we cannot
predict the order in which the mutations will occur. This means that a tumor might have mutations will that
allow it to enter the bloodstream even before it acquires mutations that allow it to break through the basement membrane and become malignant. In this case it will be primed and ready to metastasize as soon as
it becomes malignant – maybe this happened to Steve Jobs’ pancreatic tumor. Another benign tumor may
never experience the selective pressure that favors metastasis, so may remain benign or even if it turns
malignant it may stay localized. Because we can’t design a ‘recipe book’ for how tumors will behave, our
best option is to detect all tumors as early as possible.
Wo r k b o o k
Lesson 5.1
MC Questions:
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1. Why is it important to identify cancer
at an early stage?
aa. The tumor is small.
bb. To prevent the tumor turning
malignant.
cc. To prevent the tumor
metastasizing.
dd. To reduce symptoms.
Detecting the tumor in the first place needs to be individualized too: Each person is a unique combination
of appearance and behavior, and only they know what is normal for themselves, and therefore which
changes are just part of the normal ups and downs of day to day life and which might need to be
144
LESSON READINGS
investigated further. Does that mole look different than it did before? How long has that cough been
lingering? Are any changes persistent?
Physicians recommend that individuals of both sexes should perform regular self-examination of
observable organs such as skin, breast and testicles after the changes due to puberty have settled down.
The purpose of these examinations is to get a sense of how one’s normal body looks and feels, so any
changes are more obvious.
DEFINITIONS OF TERMS
Self-examination – the practice
of checking one’s to establish
normal conditions and then identify any abnormal changes.
Mole checks – Self-examination
of moles on the skin to identify changes in appearance
that might indicate malignant
changes.
Screening program – any
recommended test that is
performed on a regular basis
with the purpose of identifying
cancers at an early stage.
Baseline – The normal status
of an organ or body without any
detectable changes.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.1
For instance, skin self-examination includes “mole checks” to look for any changes in the size and shape
of moles that might indicate they have become invasive (remember the “ABCDE” system from Unit 4).
Clearly, vast areas of the skin (like the back!) are obscured, so people with large numbers of moles should
also schedule regular dermatological check ups. Breast and testicular self-examinations involve feeling
the tissue for hardened “lumpy” tissue. This is where a good idea of one’s own ‘normal’ is crucial. Lumpy
tissue, especially in the breast, is very usual in some people. Only lumps that change noticeably over
time, and then persist, are of concern.
One obvious problem with self-examination
is that many symptoms that are associated
with cancer may also occur in other diseases.
In fact if you Google headache, fatigue, fever,
weight-loss, nausea, anemia and jaundice,
cancer comes up as an option for all of them,
even though there are many other much more
likely causes, particularly infectious disease.
However, in contrast to most infectious diseases
which usually clear up in a couple of weeks with
or without treatment, cancer symptoms persist
for much longer. Again this is where your knowlFigure 1: Instructions on how to do a breast
edge of your ‘own normal’ is critically important.
self-examination. Being aware of changes in
Only you can know when the symptoms started
your body is helpful to identify formation of
and whether they have lasted longer than might
tumors prior to their spread.
be expected.
Detecting cancer: Screening methods
Self-examination is critical but limited to direct observation. Other types of physician-directed screening
programs that can access more areas and provide tissue samples for analysis are more informative
but more invasive. Just like self-exams, routine screens compare a person’s current status with a past
normal – the baseline. The goal is to identify a tumor just after it has turned malignant but before it
MC Questions:
2. What is the purpose of selfexaminations? (Circle all correct.)
aa. Familiarize self with the body to
know what is normal.
bb. Feeling a tumor reduces its size.
cc. Identify abnormalities.
dd. Reduce symptoms of cancer.
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3. True or False: Only doctors are
responsible for detecting cancer at
an early stage.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
has metastasized so it can be removed and eradicated, or to identify a benign tumor that is likely to turn
malignant. Less acceptable, but unfortunately very common, is identifying a benign tumor but having no
idea whether it will turn malignant, or identifying a malignant tumor that has already metastasized. These
are two common limitations of screening. The question of who should receive routine screens, and what
should be done with the information is another difficult one in cancer prevention and treatment. It seems
obvious that people with large numbers of moles should undergo routine screening simply because it is
impossible to self-examine all areas of one’s own body and because melanoma is such a devastating
cancer. Similarly post-puberty girls are recommended to have annual screens for abnormalities that might
lead to cervical cancer. But whether invasive screens for slow growing cancers in elderly people are
appropriate if they are more likely to die from non-cancer related causes is a matter of great debate, as we
will see. Common routine cancer screening programs include:
The Pap screen identifies abnormalities in the cervix that can lead to cervical cancer. The pap screen
is minimally invasive – a swab of the cervix
is taken and a smear of the mucus that
contains cells spread out thinly on a glass
microscope slide. The cells are stained with
dye that reveals any abnormalities including pre-malignant cells. Pap smears are
important because cervical cancer can be
caused by human papilloma virus (HPV),
an extremely common sexually transmitted infection. For this reason screening is
recommended for sexually active females,
or women with a family history of cervical
cancer. A vaccine for HPV is now available
Figure 2: Pap smears detect changes in cells
and women who have had a course of
of the cervix. A swab of tissue is taken from
vaccine are protected from HPV-induced
the cervix and viewed on the microscope to
cervical cancer.
examine for cells that appear cancerous.
Wo r k b o o k
Lesson 5.1
Mammograms use X-rays to take pictures
of breast tissues. They can be used routinely in the absence of symptoms, or as a follow-up if selfexamination has detected a suspicious lump. The low-intensity radiation in X-rays can reveal dense,
fibrous tissue as a light area within the breast in contrast with the less dense fatty tissue the breast is
mostly composed of. However the mammogram cannot tell what that tissue is, and it may be (a) normal
– many women, particularly young women, have dense breasts normally (b) a benign tumor that may or
may not turn malignant or (c) a malignant tumor that may or may not metastasize. So after a dense area is
detected a tissue sample is commonly taken to determine whether the cells in the tissue are abnormal.
MC Questions:
4. Which of the following is NOT a
screening program?
aa. Mammograms for breast cancer.
bb. Endoscopy for colon cancer.
cc. Pap smear for ovarian cancer.
dd. Rectal exam for prostate cancer.
5. Which of the following people should
have a Pap smear?
aa. Sexually active females.
bb. Women with family history of
cervical cancer.
cc. Women who haven’t had one in
the last 5 years.
dd. All of the above.
6. True or False: Mammograms should
be done on all women who are
sexually active.
aa. True.
bb. False.
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DEFINITIONS OF TERMS
Prostate screening. The prostate gland is located behind the male reproductive organs and a physician
can examine it manually by a inserting their fingers through the rectum and feeling for any abnormalities in
size, shape or texture. The prostate gland provides a good example of best intentions in screening gone
awry. Prostate cancer is quite common in elderly men, but is usually slow growing and patients often die
from other age-related causes rather than the cancer itself. This is fortunate because prostate surgery is
extremely invasive and has serious side effects such as incontinence. For a time the decision to operate
was based on a blood-based screen that detected a protein damaged prostate glands secrete. If levels of
the protein were high, surgery or invasive radiation treatment was recommended. However the prostate
secretes this protein (prostate specific antigen or PSA) whenever it is damaged or inflamed, not just when
a tumor is present, leading to many unnecessary and debilitating surgeries. Now, a ‘watchful waiting’
approach is recommended: men after age 40 who have a family history of prostate cancer and after age
50 who don’t receive annual digital rectal exams to detect changes in the prostate gland.
Endoscopy and colonoscopy are the most invasive
routine screens, that require anesthesia in order to insert
a small tube with an attached camera into either the
esophagus or the colon, (“colon endoscopy” is shortened
to “colonoscopy”). Esophageal endoscopy is used to
detect ulcers or tears in the lining of the lower esophagus,
commonly found in people with gastro-esophageal reflux
disease, in which acid in the stomach enters into the
esophagus. Ulcers are often pre-cancerous and can lead
to esophageal or stomach cancers.
Incontinence – the inability to
regulate bladder function.
Ulcers – the tear in the stomach
or lining of the digestive tract.
Polyp – a tumor protruding from
the lining of the colon.
Wo r k b o o k
Lesson 5.1
Figure 3: Colon polyp
visualized by colonoscopy.
These growths are typically
pre-cancerous tumors and
are removed if identified by a
colonoscopy.
Colonoscopy is used to detect polyps, which are small
tumors that form in the lining of the colon. If they are
detected during a colonoscopy screen the surgeon can
remove them on the spot, using the same device that holds
the camera. Polyps are often pre-cancerous and can lead
to colon cancers.
Genetic mutations. Years of research have identified gene mutations that are commonly observed in
certain types of cancer. We have investigated some of these genes throughout the module, including:
p53, Rb, and BRCA1/BRCA2. Now reliable, cheap and quick gene sequencing means it is possible to
test for inherited mutations that may predispose to developing cancer even before tumors have formed!
Sometimes mutations in a specific gene are so well correlated with a high possibility of developing a
particular kind of cancer (such as the association between mutations in the BRCA genes and breast and
ovarian cancer) that detecting this kind of mutation in a genetic screen will lead to the recommendation
MC Questions:
7. Which of the following can be
detected by an endoscopy? (Circle
all correct.)
aa. Tumors of the prostate.
bb. Polyps in the colon.
cc. Ulcers in the stomach.
dd. Tumors of the cervix.
8. What is the difference between a
screen and a diagnostic test? (Circle
all correct.)
aa. Diagnostic tests use invasive
measures.
bb. Screens are done before cancer
is observed.
cc. Diagnostic tests can identify
benign and malignant tumors.
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LESSON READINGS
that the organ should be preemptively removed, even before a tumor appears. This is particularly true if
the mutation is in the context of a family history of the cancer.
Tumor or cancer: diagnostic tests?
DEFINITIONS OF TERMS
Screens detect abnormalities by comparing current conditions to a normal baseline, but often are unable
to conclusively determine whether abnormal tissue is benign or malignant, so further follow-up diagnostic
tests are needed to complete the diagnosis of whether the abnormality is benign or malignant. There are
three major types of diagnostic tests to confirm the presence of a cancer: taking an image of the affected
organ, extracting tissue, or sampling blood.
Organ Imaging
Diagnostic test – a test
performed to identify the nature
of a tumor especially grade and
stage.
Ultrasound – a type of imaging
that uses sound waves to detect
tissue density.
MRI – magnetic resonance
imaging, a type of imaging that
uses the properties of water in a
magnetic field to visualize tissues.
PET – positron emission tomography, a type of imaging that uses
uptake of radioactive glucose to
identify metabolically active tumor
cells.
Wo r k b o o k
Lesson 5.1
Both X-rays and endoscopy are used both to screen for abnormalities, as we saw above, and also to
diagnose whether those abnormalities are benign or malignant tumors of the breast and lungs (using
X-rays) and esophageal, stomach, or colon/rectum (using endoscopy). Organ imaging is popular because
it is cheap and non-invasive but has a number of drawbacks, including undue exposure to radiation (in the
case of X-rays). Other than X-rays and endoscopy, other major types of organ imaging include:
■■ Ultrasound – uses sound waves to detect tissue density. While it is cheap and doesn’t require
radiation, it is limited to visualizing tumors of the breast, thyroid, and genital tissues.
■■ MRI – magnetic resonance imaging (MRI) pulses
radio waves into an organ that is positioned within
a strong magnetic field. The combination of the
radio waves, magnetic field and water in the body
provides an accurate image of tissues. MRIs are
expensive ($1000-$3000) and time consuming (~30
min) and limited to bone, brain, and muscle tissues.
■■ PET – positron emission tomography (PET) used
injected radioactive glucose to detect cancer cells
because they are more metabolically active than
normal cells. PET produces high quality images and
is useful because it can detect metastases, but it
uses radiation and is very expensive ($3000-$6000)
and time consuming (2-4 hrs).
Figure 4: A PET scan measures
glucose uptake into cells. Cancer
cells require more glucose to grow,
so they appear more red than
surrounding tissue. Images show
glucose uptake from two angles.
MC Questions:
9. Which of the following allows
visualization of an organ without
using radiation? (Circle all correct.)
aa. MRI.
bb. PET.
cc. Ultrasound.
dd. X-ray.
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10.Which of the following imaging
techniques can detect primary AND
secondary tumors at the same time?
aa. MRI.
bb. PET.
cc. Ultrasound.
dd. X-ray.
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Biopsies and Blood Samples
MC Questions:
Any imaging technique can only provide limited information about a tumor. Tissue biopsies, which extract
small pieces of tissue from a tumor provide better information about the organization of the cells in the
tumor and the surrounding tissue – critical to
define whether a tumor is malignant.
11. What is the main difference between
a surgical and needle biopsy? (Circle
all correct.)
aa. Size of incision.
bb. Ability to identify tumor stage.
cc. Ability to identify tumor grade.
dd. Amount of tissue collected.
DEFINITIONS OF TERMS
Biopsy – a sample of tissue
used for diagnostic purposes.
Needle biopsy – a sample of tissue extracted from the body using a needle inserted directly into
the tumor. Only a small amount of
cells is gathered.
Surgical biopsy – a sample of
tissue extracted from the body
using surgery. The sample includes both tumor and surrounding cells for diagnostic purposes.
Tumor-specific antigens –
proteins expressed by tumor cells
that are not expressed by normal
cells. They can sometimes be
secreted into the blood.
False positive – a positive result
from a diagnostic test, even
though disease is not present.
Wo r k b o o k
Lesson 5.1
Figure 5: A needle biopsy gives
information on how cells in a tumor appear,
but not whether the tumor has spread.
There are two major types of biopsies: A needle
biopsy uses a needle to remove cells from a
tumor (that was originally identified by imaging).
The cells are then visualized under the microscope. This type of biopsy provides information
on how some of the cells in the tumor look (i.e.
what grade it is) not whether the tumor has spread
or not (i.e. what stage it is). A surgical biopsy
removes a portion of the tumor including the
surrounding tissue, providing information on both
tumor grade and possibly stage.
Biopsies can provide a lot of information about the tumor and how far has progressed but are sometimes
painful or difficult, particularly if the affected organ is located in the body cavity, such as the pancreas,
liver, kidneys or difficult to access, such as the brain. In these cases, it would be preferable to sample the
blood for markers that provide indirect evidence of the tumor characteristics. Fortunately these types of
marker exists and include:
■■ Red cell count – many cancers cause anemia, or loss of red blood cells
■■ White cell count – leukemias or cancers of white blood cells, elevate white cell counts in the blood.
■■ Tumor-specific antigens – as mentioned in Unit 4 and above some tumors express specific
proteins that are not normally found in normal tissues and sometimes secrete them, so they circulate
in the blood. Examples of tumor antigens include: prostate specific antigen (PSA), alpha-feto-protein
(AFP) for liver and germ cells, and carcino-embryonic antigen (CEA) for the large bowel.
We have talked about the drawbacks of PSA above. Indeed many tumor ‘specific’ antigens, while
secreted by tumors are not ‘specific’ at all. It can also be challenging to establish a ‘normal’ baseline. As a
result it is not unusual for a blood test to inaccurately indicate presence of a tumor. This is called a “false
positive” result. False positives are a problem, particularly with cancer treatment, which is often painful
and inconvenient, and we will explore this concept in more detail in Lesson 5.2
12.Which is a marker for cancer that
can be detected from a blood test?
aa. Anemia.
bb. Tumor antigens.
cc. High immune cell count.
dd. All of the above.
13.What is the main difference between
a surgical and needle biopsy? (Circle
all correct.)
aa. Size of incision.
bb. Ability to identify tumor stage.
cc. Ability to identify tumor grade.
dd. Amount of tissue collected.
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STUDENT RESPONSES
What would the most useful routine screen for liver cancer look like? What are the strengths and weaknesses of the three most
common diagnostic tools? How could they be improved?
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Lesson 5.1
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150
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.1
DEFINITION
Baseline
The normal status of an organ or body without any detectable changes.
Biopsy
A sample of tissue used for diagnostic purposes.
Colonoscopy
The visualization of the colon or rectum using a flexible camera.
Diagnostic test
A test performed to identify the nature of a cancer.
Endoscopy
The examination of the interior of a body canal, such as the esophagus, bladder, stomach, or colon, using a
flexible camera.
False positive
A positive result from a diagnostic test, even though disease is not present.
Incontinence.
The inability to regulate bladder function
Mammogram
An X-ray examination of breast tissue intended to serve as a diagnostic test for cancers of the breast.
Mastectomy
Surgery that removes the entirety of the breast as a treatment or preventative measure for cancer.
Mole checks
Self-examination of moles on the skin to identify changes in appearance that might indicate malignant
changes.
MRI
Magnetic resonance imaging, a type of imaging that uses the properties of water in a magnetic field to
visualize tissues.
Needle biopsy
A sample of tissue extracted from the body using a needle inserted directly into the tumor. Only a small
amount of cells is gathered.
Pap smear
A diagnostic test for cervical cancer performed to identify cancerous or pre-cancerous tissue of the cervix.
PET
Positron emission tomography, a type of imaging that uses uptake of radioactive glucose to identify metabolically active tumor cells.
Polyp
A tumor protruding from the lining of the colon.
Pap smear
Any recommended test that is performed on a regular basis with the purpose of identifying cancers at an
early stage.
151
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.1
DEFINITION
Screening program
Any recommended test that is performed on a regular basis with the purpose of identifying cancers at an
early stage.
Self-examination
The practice of checking one’s body to establish normal conditions and then identify any abnormal changes.
Surgical biopsy
A sample of tissue extracted from the body using surgery. The sample includes both tumor and surrounding
cells for diagnostic purposes.
Tumor-specific antigens
Proteins expressed by tumor cells that are not expressed by normal cells. They can sometimes be secreted
into the blood.
Ulcers
The tear in the stomach or lining of the digestive tract.
Ultrasound
A type of imaging that uses sound waves to detect tissue density.
152
LESSON 5.2 WORKBOOK
What do cancer screens really tell
us?
DEFINITIONS OF TERMS
Mortality rate – The rate at
which people die from a specific
cancer.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
Treating cancer successfully requires that we are able to detect it early. As more
diagnostic techniques are developed it becomes important to understand how
reliable they are – how many cancers will they miss and how many times will they
indicate that cancer is present when it is not? This lesson discusses the concepts
of sensitivity and specificity and shows how screens can lead to ‘overdiagnosis’ and
why overdiagnosis poses a problem, using recent findings with breast and prostate
cancers as an example.
Evaluating cancer screens: specificity and sensitivity
As we have discussed in previous lessons, an abiding problem with cancer treatment is that symptoms
may appear well after the primary cancer has metastasized. When this happens it is almost inevitable
that the cancer has become more difficult, even too difficult to treat. It is clear that reliable screens to help
us identify those benign tumors that are going to become malignant and malignant tumors before they
metastasize are key. In the last lesson we began to examine the screening programs that are available
to identify tumors at these early stages. But in order to evaluate how useful a screening program may be
we need to have more information than how it works. We need to know whether it is effective in detecting
tumors at the important stages before metastasis and whether it targets tumors for treatment that would
never have been problematic. These kinds of evaluation pose another problem – the difference between
population statistics and individual behavior. When a program is evaluated on the basis of its effectiveness
for the population as a whole it gives no information to an individual as to how they themselves might fare.
Sometimes an individual may fare in the same way as most of the population. Other times they may act
like outliers and have an experience very different from the population as a whole. This is another challenge that we need to deal with when assessing which screens and treatments are most effective.
Notes:
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LESSON READINGS
DEFINITIONS OF TERMS
Specificity – how accurate a
screen is in identifying abnormal
cells.
False negatives – Those cells
(or people) that are abnormal,
but are falsely identified as being
normal.
Sensitivity – how likely a screen
is identify abnormal cells.
False positives – Those cells
(or people) that are normal, but
are falsely identified as being
abnormal.
Let’s assume we are
evaluating two screens
that have been designed,
like the Pap smear, to
detect pre-cancerous and
malignant cells. Let’s say
one screen detects the
abnormal cells by dying
a protein in the cells red,
while the second screen
detects abnormal cells by
their shape. We evaluate
the screens using two
criteria.
1. According to Figure 1, how many
people are false positives detected
by Screen 2?
aa. 20%.
bb. 30%.
cc. 70%.
dd. 80%.
Figure 1: Two sample screens for a population. A highly
specific screen (Screen 1) will only identify diseased individuals,
but may miss people who are diseased that do not test positive
for the screen. A highly sensitive screen (Screen 2) will identify
everyone with the disease, but may falsely identify some people
as having disease that actually don’t.
The specificity of a
screen tells us how
accurate the screen
is in identifying abnormal cells. The red screen would be good at identifying cells that are red, but will
miss cells that are abnormal - if they aren’t strongly red for example. These cells will be called ‘false
negatives’; that is, they are abnormal, but the screen hasn’t detected them.
On the other hand the sensitivity of a screen tells us how likely the screen is to identify abnormal cells. A
cell shape screen will identify cells that are clearly abnormal well, but it may be more likely to define cells
as abnormal that are really normal. These cells will be called “false positives”.
Figure 1 compares how two different screens on a population of people some of whom are normal
(green smiley faces) and some of whom are sick (orange sad faces).
■■ Screen 1 is in purple. Out of the 10 people in the population it has correctly identified 20% as sick
and correctly identified all the normal people. However it has missed 20% of the population. These
false negatives are sick but think they’re normal.
■■ Screen 2 is in red. Out of the 10 people in the population it has detected everyone who is sick, but it
has also identified 30% of the normal population as sick These false positives are really normal.
Wo r k b o o k
Lesson 5.2
MC Questions:
In reality all screens struggle to achieve the right balance between false negatives and positives – but
what is right?
2. True or False: The best screens will
have no false positives and no false
negatives
aa. True.
bb. False.
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LESSON READINGS
Screening outcomes: the problem of overdiagnosis
DEFINITIONS OF TERMS
Non-progressing cancers –
cancers that have evolved such
that they can no longer grow or
spread to other tissues. These
cancers will not cause disease.
Overdiagnosis of cancer –
diagnosis of cancer that will never
be life-threatening.
Wo r k b o o k
Lesson 5.2
One important take-home message
from this module is that cancer is the
end-point of an evolutionary process
that starts with a normal cell becoming able to hyperproliferate and ends
with metastases. But there is no
single path from benign to malignant
and metastatic. Figure 1 illustrates
four distinct ways the disease could
progress from an initial screen
(indicated by the ‘abnormal cell’ in the
bottom left. In the 1st model ‘very fast’
the cancers progresses very quickly.
Figure 2: Model for progression of abnormal
(cancer) cells. Fast growing tumors will be likely to
Individuals will likely display sympcause disease and death from cancers, while patients
toms very quickly after the cancer
with slow growing tumors and non-progressing
has been detected and are likely to
tumors will likely die from unrelated causes before
die if they are not treated. Clearly they
they will die from cancer.
would suffer greatly if they were a
false negative on the screen, as would
individuals in the 2nd model ‘fast’. On the other hand, in the 3rd model ‘slow’ and the 4th model ‘nonprogressing’ the cancer is growing so slowly that they will more likely to die from unrelated causes (like
age) than they will from the cancer itself. This group would not suffer physically at all if their cancer was
never identified. Not only that they will also be spared considerable non-productive anxiety over the years.
The $64,000 question an informed patient would want answered is: ‘Before I get tested how can you tell
which model my cancer would fall under if it was detected?’. It should be very clear from this module that
we are still nowhere near having an answer to that critical question. Because of this the strategy that has
been used is to screen and treat all cancers as though they fall into the worst case scenario – that is if a
screen detects evidence of a benign tumor, treat it as if it will become malignant, if it detects evidence of
a malignant tumor treat it as if it will metastasize. This strategy would be appropriate for Models 1 and 2,
but not for Models 3 and 4. The problem it causes has been termed overdiagnosis. Overdiagnosis then
results in overtreatment. We can easily understand why overtreatment is problematic simply by knowing
that the three major cancer treatments we have available, namely surgery, radiation, and chemotherapy
are commonly referred to as “slash, burn, and poison”. Because cancer treatments themselves are so
painful and traumatic, the decisions to treat when it is not required should not be taken lightly..
MC Questions:
3. True or False: All cancers will
progress to metastasis.
aa. True.
bb. False.
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LESSON READINGS
Cancer overdiagnosis and
overtreatment
Breast Cancer
DEFINITIONS OF TERMS
US Preventative Services
Task Force (USPSTF) – a
governmental agency responsible for determining guidelines
for screening programs for the
population.
Prostate-specific antigen – a
protein that is produced by prostate cancer cells that is secreted
into the blood. This protein has
been used as a diagnostic test for
prostate cancer.
Wo r k b o o k
Lesson 5.2
Mammograms have been used as routine
screens for detection of breast tumors since the
1980s. Programs to raise awareness of breast
cancer have promoted the notion that ‘early
detection is the key to a cure for breast cancer’.
And the best method for early detection was
a yearly mammogram for every woman over
the age of 40. Recently, the US Preventative
Services Task Force (USPSTF), a governmental agency charged with determining the
guidelines for screening programs throughout
the country, changed these recommendations.
Now mammograms are only recommended for
women over the age of 50 and then only every
1-2 years, not necessarily annually.
Figure 3: Since mammograms were
introduced as routine screens in the 70s,
there has been a rise in detected cancer,
but this rise has not increased in a rise of
late stage cancers. We are identifying many
more cancers, but these may never become
problematic.
These changes left many people perplexed. What had happened? Was early detection no longer the
key to cure? In fact the USPSTF report provided good evidence that the original mammogram screening
program had detected many more early stage breast tumors and cancers (which is why the blue line in
Figure 1 rises). However this increased detection hadn’t improved the rate at which late stage cancers
were diagnosed (the brown line in Figure 1 stays flat). Why not? The problem comes in connecting
detection with cure. The USPSTF realized that most of the early stage tumors the mammogram
screening program was detecting would never become the late stage aggressive metastatic cancers
that cause severe disease (if they did the brown line in Figure 1 would fall). So, the screens were actually
overdiagnosing cancer, by identifying women under age 50 who had malignant tumors in the Model 3 and
Model 4 category. Many of those women were often also overtreated with extensive surgeries leading to
extreme anxiety.
MC Questions:
4. Overdiagnosis is a problem because:
(Circle all correct.)
aa. Screens will falsely identify
people with cancer who don’t
have disease.
bb. People don’t need to know if
they have cancer.
cc. Cancer treatment is so painful
and traumatic.
dd. Some cancers will not ever
metastasize and cause severe
symptoms.
5. Why did the USPSTF change
recommendations for
mammograms? (Circle all correct.)
aa. They were trying to reduce
overdiagnosis of breast cancer.
bb. Mammograms are unaffordable
under most health care plans.
cc. The identification of late stage
cancer was not being reduced
by mammogram screenings.
dd. Early stage cancers were not
being identified early enough.
6. True or False: Screening
recommendations for the population
are always under review.
aa. True.
bb. False.
156
LESSON READINGS
Prostate Cancer
DEFINITIONS OF TERMS
Double mastectomy – surgical
removal of both breasts.
Prostate cancer is extremely common – it has been estimated that 80% of men over the age of 80 have a
prostate cancer diagnosis. The ‘early detection, early cure’ principle pushed for development of a routine
screen. The prostate gland supplies the fluid for semen, and produces a protein called prostate-specific
antigen (PSA), which promotes sperm movement. The prostate normally secretes low levels of PSA
into the blood. Whenever the prostate is damaged, the secreted PSA levels in the blood rise. This is
particularly true when prostate cells are hyperproliferating. Because of this, men over the age of 50 were
recommended to have regular screens for blood PSA levels. If levels were high they were recommended
for either surgery or radiation. Both of these treatment options are highly unpleasant. Because of the
location of the prostate close to the urinary tract and genitals surgery commonly left men incontinent or
impotent or both. Recently these recommendations have also changed and the USPSTF now no longer
recommends PSA screens at all. Why? Two main reasons: First, prostate glands increase secretion of
PSA whenever they are damaged, not just during cancer and many men, particularly aging men have
high levels of PSA for other reasons such as because the prostate is inflamed. Second even though
prostate cancer might be present and correlated with high PSA levels, this does not necessarily mean that
a cancer will progress. In fact most prostate cancers fall solidly in Model 4 – they never progress to severe
disease. The recommended approach now is ‘watchful waiting’. The physician will regularly monitor a
prostate tumor and only perform surgery or radiation treatment when there is evidence it is growing.
Genetic Screens
Cancer research has pinpointed mutations in several genes that are hallmarks for cancer. Individuals
having these mutations may be predisposed to developing cancer since their cells are already ‘on the
way’ to becoming able to hyperproliferate. In particular certain combinations of mutations have clearly
been associated with increased incidence (mutations to both BRCA 1 and 2 for example predispose
to both breast and ovarian cancer). Angelina Jolie inherited both BRCA mutations and chose to have
prophylactic surgery - she underwent a double mastectomy thereby reducing her risk of developing
breast cancer by over 90%. However single mutations may never progress to cancer formation, and
hence prophylactic surgery in this case is likely to be overtreatment.
Wo r k b o o k
Lesson 5.2
As we’ve described in this module, it takes many steps for a tumor to become a cancer, and we are
not able to predict what path any once cell will take. While some people might favor life-altering cancer
treatment under any conditions, others might alter their treatment plan if they understand when receiving
a diagnosis of cancer does not necessarily meant developing a life-threatening disease. Individual health
choices may vary from what the USPSTF recommends, but it is important that these choices are made
through informed decisions.
MC Questions:
7. Which of the following is a
reason that PSA screens are not
recommended for prostate cancer?
(Circle all correct.)
aa. The PSA test is not very accurate
in identifying PSA levels.
bb. Prostate cancer is a slowgrowing disease.
cc. Many people have high blood
PSA levels normally.
dd. PSA is secreted non-specifically.
8. True or false: A genetic screen of
your DNA sequence will reduce your
risk of cancer overdiagnosis.
aa. True.
bb. False.
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STUDENT RESPONSES
Explain how specificity and sensitivity are a trade-off in cancer screens. Also, what instances would you want a highly specific
cancer screen? When would you want a highly sensitive cancer screen? (Hint – think about severity of disease vs. severity of
treatment.)
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Lesson 5.2
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158
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
DEFINITION
Double mastectomy
Surgical removal of both breasts.
False negatives
Those cells (or people) that are abnormal, but are falsely identified as being normal.
False positive
Those cells (or people) that are normal, but are falsely identified as being abnormal.
Non-progressing cancers
Cancers that have evolved such that they can no longer grow or spread to other tissues. These cancers will
not cause disease.
Overdiagnosis of cancer
Diagnosis of cancer that will never be life-threatening.
Prostate-specific antigen
A protein that is produced by prostate cancer cells that is secreted into the blood. This protein has been
used as a diagnostic test for prostate cancer.
Sensitivity
How likely a screen is identify abnormal cells.
Specificity
How accurate a screen is in identifying abnormal cells (or people).
US Preventative Services
Task Force (USPSTF)
A governmental agency responsible for determining guidelines for screening programs for the population.
159
LESSON 5.3 WORKBOOK
How do we treat cancer?
DEFINITIONS OF TERMS
Mastectomy – surgical removal
of the all or part of a breast.
For a complete list of defined
terms, see the Glossary.
We can identify two challenges with cancer
treatment: First, we often cannot tell whether a tumor
that has been diagnosed will ever give rise to lifethreatening disease — this means that overtreatment
is a danger. Second, available treatments are usually
not tailored to specific tumors - this means they are
sometimes not completely effective, especially for
metastases. This lesson examines the strengths and
weaknesses of the three common cancer
treatments: surgery, radiation and chemotherapy.
Cancer treatment: Surgery
Wo r k b o o k
Lesson 5.3
Antonie van Leeuwenhoek’s discovery in the 17th century that living organisms are composed of cells
revolutionized biology and medicine, especially cancer: if cancer is caused by an overgrowth of cells, not
an accumulation of black bile, why not just remove these rogue cells? Fortunately the barber-surgeons
were prepared to take on the job. While these professionals principally specialized in cutting hair, they
had the tools to remove other organs, when necessary. Not surprisingly the outcomes of these ‘surgeries’
were often very disfiguring. Moreover, hygiene was poor and patients that didn’t die on the ‘operating table’
usually died later of infection. On the rare occasions that patients survived the tumors, often recurred,
sometimes far removed from the original site. We now understand that even when a primary tumor has
been removed completely, cancer cells that metastasized previously will persist. But at the time it was
believed that the cancer had returned because the surgery had not had left some cancer cells behind at
the primary site. The response was to remove more and more cells around the primary site. For instance
surgery to remove a tumor from the breast would not only eliminate the breast entirely, but would also
remove the underlying muscle tissue (called a radical mastectomy). Clearly removing the muscle would
have no effect on metastatic cells that have already migrated to bone – a preferred sites for secondary
breast tumors, as we learned in Unit 4.
MC Questions:
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1. Why did cancers return following
surgery from barber-surgeons?
aa. They did not have proper tools.
bb. They did not know how to
perform mastectomies.
cc. Surgery did not remove all
cancer cells in the organ.
dd. Surgery could not remove
metastatic cells.
160
LESSON READINGS
DEFINITIONS OF TERMS
Lumpectomy – surgical removal
of a tumor in the breast together
with some surrounding tissue.
Tumorectomy – general term for
the surgical removal of a tumor
and surrounding tissue.
Overtreatment –medical interventions to treat cancer that are
more invasive than is necessary.
An increased understanding of how tumors develop
has led to a re-evaluation of the mastectomy. Now we
understand that a limited surgery to remove the tumor
and surrounding tissue (known as the tumor margin)
can be sufficient. This kind of surgery, known as a
lumpectomy is highly effective at preventing invasive
breast cancer provided the tumor has not metastasized before the surgery is carried out. In some cases
however treatment decisions do not follow best medical practice. For example, some insurers won’t pay for
breast reconstruction unless a full mastectomy has
performed leading some women to elect to undergo a
full mastectomy even when not strictly necessary. This
is another example of overtreatment.
Figure 1: The so-called ’Halstead’
mastectomy removed the underlying muscle in addition to the breast.
Women often were unable to raise
their arms afterwards.Yet it would not
prevent metastases.
The general term for removal of a tumor and
surrounding tissue is tumorectomy. Tumorectomy is clearly required when a tumor occurs in an essential
organ such as the brain and liver. On the other hand, full organ removal maybe performed if the organ is
readily accessible and not essential for health, such as the testes or ovaries.
Of course surgery has improved considerably since the time of the barber-surgeons. New techniques y
make surgery more precise and less invasive, often requiring only a minor incision. When combined with
robots assisted by computers previously inaccessible tumors can be visualized and removed. But sometimes these improvements themselves have unintended consequences. Many women suffer from benign
tumors of the uterus called fibroids. This has improved our ability to gain access into tissues and perform
surgery under the control of a computer using Because fibroids are often debilitating and may affect fertility it has been a major goal of surgeons to develop a method to remove them without affecting the uterus.
One such method involved inserting essentially a tiny ‘immersion blender’ into the uterus and chopping
the fibroid up into tiny pieces that could be suctioned out with ease. Unfortunately, some of those fibroids
harbored malignant cells that were dispersed by the blender action, in rare cases causing uterine cancer.
Because of this the technique was re-evaluated and is currently discouraged.
Cancer treatment: radiation
Wo r k b o o k
Lesson 5.3
Not all tumors are accessible to surgery because of their location. One obvious example is the brain.
A tumor buried deep in the brain will never be available to even a tiny robot because the path the robot
would have to take to gain access to the tumor would destroy important functional areas and brain
neurons, unlike epithelia, are unable to renew themselves. A further problem with the most common form
MC Questions:
2. Which of the following might
increase your risk of developing
cancer?
aa. Heavy metals.
bb. Smoking.
cc. Excessive tanning.
dd. All of the above.
3. Why is 'overtreatment' a concern for
cancer treatment?
aa. People can’t afford the
treatments.
bb. Milder forms of cancers are
being treated as more severe.
cc. Insurance companies make
more money by treating more
people.
dd. People are being treated for
cancer when they don’t have it.
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MC Questions:
of brain cancer, glioblastoma, is that the malignant cells
migrate into the surrounding tissue meaning it is impossible
to remove them all by surgery. The preferred treatment for
patients who have tumors that are inaccessible to surgery
is radiation therapy. The use of radiation to treat cancer
started with the work of Pierre and Marie Curie (who isolated
radium) and Wilhelm Roentgen (who discovered X-rays).
DEFINITIONS OF TERMS
Radiation therapy – the use of
radiation treatment to control the
growth of or kill malignant cells in
the body.
Radiotherapy – a type of radiation therapy that focuses a beam
of X-ray radiation on cells within a
specific region of the body.
Brachytherapy – a type of radiation therapy that uses small radioactive pellets surgically implanted
within a tumor to kill cells.
Wo r k b o o k
Lesson 5.3
Radiation, particularly X-ray radiation kills cells by promoting
DNA damage that leads to apoptosis. It successfully kills even
cancer cells that have inhibited the apoptosis pathway. Radiation can appear to actually melt tumors, and has been used
very successfully to treat breast cancers and lymphomas.
However, initial treatments that used high levels of radiation
could also affect normal cells – either killing them or mutating their DNA and causing transformation and additional
malignancy.
Figure 2: Radiotherapy
focuses radiation into a focal
point in the body, thereby
destroying a focal tumor.
The indiscriminate effects of high levels of radiation on both normal cells and cancer cells was a major
drawback when radiation was first used, but the initial treatment methods by either reducing the dose of
radiation and providing the patient with multiple treatments (typically 5-8 weeks) and/or focusing the beam
to target cancer cells. Radiotherapy is effective for
many skin cancers, some head and neck cancers,
and in combination with surgery can completely kill
cancer cells in a tissue like the breast.. Even so,
radiation cannot kill metastatic cells that are widely
dispersed in the blood or lymph.
An alternative form of radiation therapy is called
brachytherapy, in which pellets of radioactive
chemicals such as iridium, iodine, or palladium
are inserted into a tumor. These pellets release a
Figure 3: Brachytherapy requires
measured dose of radiation that kills nearby cells,
insertion of radioactive pellets into a
tumor that degrade a tumor.
which are hopefully mostly tumor cells. While
radiotherapy is better suited for spherical tumors,
brachytherapy is useful for tumors that are irregular
in shape. Brachytherapy can dose the interior of a tumor with radiation more precisely than a beam of
radiation but because it is so localized it is likely to miss cancer cells at the edge of the tumor. Since these
are often the most likely to metastasize this can be problematic.
4. How does radiation therapy work?
(Circle all correct.)
aa. Radiation damages DNA.
bb. Radiation inhibits growth
signaling.
cc. Radiation activates apoptosis.
dd. Radiation increases temperature
of cancer cells.
5. Which of the following is a way
that radiotherapy is different from
brachytherapy? (Circle all correct.)
aa. Brachytherapy cannot treat
spherical tumors.
bb. Radiotherapy uses X-ray
radiation.
cc. Brachytherapy is invasive.
dd. Radiotherapy damages DNA.
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Radiation therapy is very effective when used as a combined approach along with surgery and/or
chemotherapy. Its future lies in developing techniques that focus the radiation more precisely. But
radiation will always affect both tumor and normal cells, and as it stands now it can never be specific for
cancer cells.
Cancer treatment: chemotherapy
DEFINITIONS OF TERMS
Chemotherapy – the use of
chemical substances to kill malignant and metastatic cancer cells.
Leukemias – a group of cancers
of white blood cells that typically
originate in the bone marrow.
Remission – reduction of cancer
symptoms that indicates absence
of disease.
Cancer stem cells – a type of
cancer cell that gives rise to drug
resistant tumors.
Selective pressure – any external cause that favors the ability of
a subset of cells to replicate.
We learned in Unit 4 that malignant tumors turn into cancer when they metastasize, and that metastatic
cells circulate in the bloodstream or lymph as they seek a niche where they can establish a secondary
tumor. In this case even if surgery or radiation or even the immune system successfully destroys the
primary tumor, the cancer will not be eradicated until the metastatic cells are also destroyed. Developing
methods to kill the all the cancer cells has been a major challenge in cancer therapy.
Chemotherapy, uses chemical compounds to poison cancer cells. The idea arose in the mid-20th
century after it had been noted that survivors of the mustard gas attack during the battle of Ypres in World
War I had very few white blood cells left in their bone marrow. The observation was followed up, and it
was discovered that intravenous nitrogen mustard (the active ingredient in mustard gas) could be used to
kill malignant white blood cells (leukemias).
The discovery that a chemical could kill cancer cells led to development of other types of drugs that
broadly fall into four categories:
■■ Antimetabolites are drugs that inhibit DNA or RNA synthesis such as methotrexate and
6-mercaptopurine.
■■ DNA damaging agents are drugs that damage existing DNA such as nitrogen mustard and
platinum derivatives like cisplatin.
■■ Mitosis inhibitors are drugs that prevent chromosomes separating during mitosis such as vincristine, vinblastine, and taxol.
■■ Immune system inhibitors are drugs that inhibit chronic inflammation such as prednisone.
Wo r k b o o k
Lesson 5.3
A single chemotherapeutic drug used on its own can often be very successful at killing the primary tumor,
even inducing a cancer-free state or remission. However these remissions are usually brief. The problem
has been the extent to which cancer is a product of evolution. When a single drug is used, the selective
pressure it induces will favor the few cells in the tumor that are already resistant to the drug, in a similar
way that a population of bacteria evolves to become resistant to antibiotics. These resistant cells that
MC Questions:
6. True or False: Some chemotherapies
were once used as a poison.
aa. True.
bb. False.
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chemotherapies? (Circle all correct.)
aa. Inhibitors of DNA replication.
bb. Inhibitors of DNA mutation.
cc. Inhibitors of gene expression.
dd. Inhibitors of metastasis.
8. True or false: Cancer cells develop
chemotherapy resistance by
randomly acquiring mutations
that make them resistant to
chemotherapy after exposure to that
drug.
aa. True.
bb. False.
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are present before chemotherapy and that survive the treatment are called cancer stem cells. They
generate a population of cancer cells that are now resistant to that treatment, leading to recurrence of the
cancer or relapse.
DEFINITIONS OF TERMS
Relapse – the return of
symptoms of cancer following a
period of remission.
Remission – reduction of cancer
symptoms that indicates absence
of disease.
Combinatorial chemotherapy
– the use of multiple drugs
in parallel or in sequence to
treat a cancer with the hope of
preventing development of drug
resistance.
Wo r k b o o k
Lesson 5.3
One approach to handling drug resistance is to treat cancer just as we would treat a bacterial infection.
For example, Tuberculosis (TB), a disease caused by the bacteria Mycobacterium tuberculosis, almost
always becomes drug-resistant if it is treated with only one drug. Because of this, tuberculosis is always
treated with a mixture of different antibiotics, each of which targets a different aspect of the bacterial
life cycle. While it is easy for Mycobacteria to acquire resistance to one drug, it is more difficult to find a
bacterium that has acquired mutations to escape the toxic effects of multiple different antibiotics. In fact
chemotherapy that uses mixtures of drugs each of which target a different aspect of cancer cell behavior
and called combinatorial chemotherapy has been quite successful.
However chemotherapeutic drugs are poisons. Just as radiation kills both cancer cells and normal cells,
so chemotherapeutic drugs will kill both cancer cells and normal cells that have similar properties to
cancer cells. For example, chemotherapeutic drugs that target cancer
cell replication will also target normal
cells that are replicating rapidly. For
instance, blood forming cells, cells on
the surface of the skin, hair cells, and
mucosal cells lining the mouth, throat,
stomach, bowel, and air passages,
all divide rapidly as part of their
normal functions, and so will also be
damaged by chemotherapeutic drugs.
Figure 5: Gleevac, a targeted chemotherapy,
Because of this, chemotherapies
has been efficiently shown to kill leukemias and
have many unpleasant side effects
gastro-intestinal tumors (GIST), and possibly other
including: anemia, weakening of the
cancers, with little sign of cancer relapse.
immune system, hair loss, nausea, and
vomiting.
In some cases the side effects of the therapy can be as severe as the disease itself. Because of this, ‘next
generation’ chemotherapies are being designed that target cancer cell functions or genes more specifically in the hope of reducing these unpleasant side effects.
MC Questions:
9. Why are there side effects of
chemotherapy when used in cancer
treatment?
aa. Chemotherapy spreads radiation
damage in the body.
bb. Chemotherapy only targets fast
growing cells, not cancer cells.
cc. Chemotherapy can enter tissues
non-specifically.
dd. Chemotherapy dosages have
not been optimized for humans.
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10.How are next generation
chemotherapies better than previous
chemotherapies? (Circle all correct.)
aa. They target oncogenes
specifically.
bb. They damage DNA faster.
cc. They inhibit metastasis.
dd. They improve immune killing of
cells.
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Some of the major classes of next generation cancer therapies include:
■■ Angiogenesis inhibitors are drugs that prevent blood vessels gaining access to tumors, such as
Avastin.
■■ Oncogene inhibitors are drugs that inhibit mutated proto-oncogene signaling such as Gleevec.
■■ Immunotherapies are drugs that promote immune killing of cancer cells such as Herceptin.
These new advances in anti-cancer chemotherapy show great promise. However, like other chemotherapy strategies, they don’t work well in isolation. Multiple strategies are needed that will clear the
primary solid tumor (such as surgery, radiotherapy) and then target any remaining metastatic cells (such
as chemotherapeutic drugs). Alongside improvements in therapy, detection must be optimized so that we
can identify the cells likely to mutate rapidly and become malignant in plenty of time. The future of cancer
therapy looks brighter now we recognize the extent that it is a disease of evolution.
Wo r k b o o k
Lesson 5.3
Notes:
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STUDENT RESPONSES
List one strength and one weakness of each of the three major types of cancer treatment.
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Wo r k b o o k
Lesson 5.3
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.3
DEFINITION
Brachytherapy
A type of radiation therapy that uses small radioactive pellets surgically implanted within a tumor to kill cells.
Cancer stem cells
A type of cancer cell that gives rise to drug resistant tumors.
Chemotherapy
The use of chemical substances to kill malignant and metastatic cancer cells.
Combinatorial
chemotherapy
The use of multiple drugs in parallel or in sequence to treat a cancer with the hope of preventing development of drug resistance.
Leukemias
A group of cancers of white blood cells that typically originate in the bone marrow.
Lumpectomy
Surgical removal of a tumor in the breast together with some surrounding tissue.
Mastectomy
Surgical removal of all or part of a breast.
Overtreatment
Medical interventions to treat cancer that are more invasive than is necessary.
Radiation therapy
The use of radiation treatment to control the growth of or kill malignant cells in the body.
Radiotherapy
A type of radiation therapy that focuses a beam of X-ray radiation on cells within a specific region of the
body.
Relapse
The return of symptoms of cancer following a period of remission.
Remission
Reduction of cancer symptoms that indicates absence of disease.
Selective pressure
Any external cause that favors the ability of a subset of cells to replicate.
Tumorectomy
General term for the surgical removal of a tumor and surrounding tissue.
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LESSON 5.4 WORKBOOK
What are the consequences of
cancer and cancer treatment?
DEFINITIONS OF TERMS
Remission – the reduction of
cancer symptoms, often considered being “cancer-free”
Relapse – the return of symptoms of cancer following a period
of being disease-free.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.4
The previous lesson on cancer treatment compared the benefits and risks of three
types of cancer treatments that focus on the cancer cells themselves. However
cancer as a disease affects more than the malignant cells themselves. This lesson
will focus on the strategies that are available to treat the symptoms of cancer rather
than the cells themselves, and will also discuss strategies that can play a role in
preventing cancer developing in the first place.
Not all cancers respond to treatment
For most of history cancer was considered to be an untreatable disease, and it has only been within the
last few hundred years that the potential to treat, if not cure, has been realized. In fact the three most
successful types of cancer treatment we have available, surgery, radiation, and chemotherapy were
only developed within the last 100 years. It has become clear however that these treatments are still not
enough. Some cancers respond to them while others, particularly metastases do not. Understanding how
and why some cancers are so resistant to treatment is a major focus of cancer research.
As we saw in the last lesson we consider cancer has entered remission following treatment if detection
methods can find no evidence of the primary tumor and if disease symptoms have been eliminated or
much reduced. Cancers that are detected and treated early enough that they are not yet metastatic often
enter full remission. However even cancers that are detected early may only enter partial remission if
they are already metastatic. In this case the cells that have been spared may not be detectable but they
will continue to proliferate and the cancer will return once the number of cells or tumor burden increases.
In the meantime the disease symptoms may be reduced or even eliminated, but this is temporary until the
cancer recurs and the patient enters relapse.
MC Questions:
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1. Which of the following describes the
outcome of a cancer that is 'cured'?
aa. Reduction.
bb. Relapse.
cc. Remission.
dd. Return.
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LESSON READINGS
Notes:
Whether a cancer will remain in remission or will relapse is usually almost impossible to predict. From
what we have learned throughout this module it should be clear that the reason for this is that each
cancer evolves as a response to the selective pressures it is experiencing and this can be very variable
between individual tumors or even between cells in a single tumor. The flip side of this random evolution
however is that individual metastatic cells may very well randomly evolve traits that prevent them from
forming secondary tumors. In this case the patient will seem like they are experiencing full remission, even
though many metastatic cancer cells remain in the body. If these cells remain functionally useless they will
likely be killed by the immune system over time.
DEFINITIONS OF TERMS
Conventional treatment – any
treatment typically used by medical professionals to treat cancer
(i.e. surgery, radiation, and /or
chemotherapy).
Intervention study – a study
where one group is given a treatment to evaluate the effect of that
treatment on people.
Wo r k b o o k
Lesson 5.4
Figure 1: A model for the evolution of cancer
and how different treatments target cancer cells.
While surgery is able to remove all cancer cells
from an organ, it cannot remove metastatic cells,
much like radiation therapy (Rad.), which only
targets fast growing cells that are not metastatic.
Chemotherapy (Chemo.) can kill some metastatic
cells and some cells of the tumor, but is more
specific and limited to a subset of cells sensitive to
the drug.
Figure 1 shows transformation of a
normal cell over time, with the boxes
indicating the types of cells each type
of therapy targets. Surgery is the only
therapy that does not target how a
cancer cell functions and so it can
effectively remove all cancer cells in a
primary tumor, but not any metastatic
cells. Chemotherapy can kill metastatic
cells except those cells that resistant to
the chemotherapy (the grey metastatic
cell in the picture). If these resistant
cells are capable of entering secondary organs, they are likely to lead
to relapse. However, if they acquire
mutations that prevent them exiting
the bloodstream or entering organs,
remission will persist.
Whether a cancer will go into remission
or relapse depends most of all on
the driver mutations (red arrows in
Figure 1) that allow the cancer cells
to acquire traits that will overcome
selective pressure. Figuring out which
mutations are drivers in the hope of
developing more specific drugs is
another intense area of research.
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LESSON READINGS
DEFINITIONS OF TERMS
Alternative treatment – any
treatment that is not a mainstream treatment to cancer (i.e.
not surgery, radiation, chemotherapy) that is used instead of a
mainstream treatment.
Complementary treatment
– any treatment that is not a
mainstream treatment to cancer
(i.e. not surgery, radiation, chemotherapy) that is used along with a
mainstream treatment.
Antioxidant – a molecule that
inhibits the activity of reactive
oxygen species to damage DNA.
Anti-angiogenic compound
– any chemical that inhibits the
growth of blood vessels.
Wo r k b o o k
Lesson 5.4
Treating cancer as a disease
MC Questions:
Surgery, chemotherapy and radiation therapy are considered conventional treatments for cancer because their
effects have been rigorously examined through numerous
interventional studies. As we learned in the Metabolic
Disorders module, intervention studies are the gold standard
for determining whether a treatment is effective. In these
studies a population with a disease is provided with a treatment and the outcome is compared with a well-matched
control group who also have the disease but who don’t
receive the treatment, or receive a different treatment whose
outcomes are well known. Without this kind of intervenFigure 2: Yoga is one type of
tion study it is impossible to know whether any positive
alternative treatment that boosts
outcome is caused by the treatment or just correlated with
energy and helps the immune
it. Few of the many cancer ‘cures’ reported an advertised
system in cancer treatment.
on the internet and in the non-scientific media have been
subjected to this level of scrutiny and so it is impossible to
know what the enthusiastic endorsements these alternative
treatments often receive really mean. Some alternative treatments that have been studied — such as
the active ingredient in apricot pits – have not stood up to rigorous scrutiny, others — such as the Gerson
treatment, a strict organic diet with frequent coffee enemas, have never been examined. Patients who
rely exclusively on these kinds of alternative treatments are therefore taking a risk. In most cases it makes
no difference whether patients receiving conventional treatments also pursue alternative treatments, but
in some cases they may interfere with the conventional therapy. It is for this reason that physicians ask
patients to inform them of all the therapies they are using.
2. What would you need to show an
alternative treatment is a useful
strategy to treat cancer? (Circle all
correct.)
aa. Evidence of efficacy in
intervention study.
bb. Number of people using
treatment.
cc. Number of articles written about
treatment.
dd. A mechanism to explain how
treatment works.
However, there are intervention studies that show some alternative treatments do work. These include
yoga, exercise, acupuncture, acupressure, hypnosis, massage, and musical therapy. It is unlikely that
these alternative approaches will lead to full cancer remission without the assistance of surgery, radiation, and chemotherapy, which is why these therapies are called complementary treatments. These
approaches may make the painful and traumatic process of mainstream cancer treatment more tolerable.
These complementary treatments have also been shown to improve the efficacy of the immune system,
which may help conventional treatments achieve cancer remission.
Finally, regulation of diet has been shown to be useful in improving cancer treatment outcomes.
Chemotherapy and radiation therapy have very toxic effects on the body, and consuming appropriate
nutrients is essential to recovering from their side effects.
3. True or false: Yoga, exercise, and
massage will improve the efficacy of
conventional treatments if performed
with these treatments.
aa. True.
bb. False.
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DEFINITIONS OF TERMS
Curative treatment – any type
of medical care given where a
cure to disease is considered an
achievable goal.
Diet also plays an important role in cancer prevention. For instance, a high fiber diet correlates with
protection against bowel cancer, but how this protection occurs is unclear. Also, consumption of foods
rich in antioxidants such as fish, tomatoes, legumes (peas, beans and soy), and dark chocolate, along
with drinking green tea and red wine has been shown to decrease cancer risk. Antioxidants are useful to
prevent cancer because they help prevent damage to DNA by carcinogens. Foods rich in antioxidants
are also known to contain natural anti-angiogenic compounds. So, consumption of foods that prevent
DNA damage and decrease angiogenesis is likely to decrease the development and spread of cancer.
4. True or False: Controlling what we
eat can prevent the development
AND progression of cancer.
aa. True.
bb. False.
Lastly, chronic infection by pathogens have been linked to certain types of cancer. For instance, Hepatitis
B is a known cause of liver cancer, and human papilloma virus (HPV) causes cervical cancer and
some oral cancers. These cancers can be easily avoided by vaccination against the virus. Furthermore,
Helicobacter pylori infection is responsible for an estimated 70-90% of all stomach cancers. Antibiotic
treatment of H. pylori before it becomes chronic is a good way to decrease the chance of developing
stomach cancer. Simple approaches to prevent infection are a good way of reducing cancer risk
significantly.
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Palliative treatment – treatment
for a disease that is considered
uncurable where the goal is to
reduce symptoms and decrease
pain and stress associated with
disease.
In conclusion, there are many steps that we can make to limit the development of early-onset cancer that
appears due to environmental causes and pathogens. Among these are:
Hospice – a program /shelter
that provides care to decrease
pain and symptoms for patients
as well as addressing emotional
and spiritual needs of the patient.
■■ Not smoking;
■■ Consuming less refined or fatty foods;
■■ Increasing exercise;
■■ Limiting exposure to UV radiation;
■■ Drinking less alcohol; and
■■ Getting vaccinated.
Much as we saw in Unit 1, these approaches will not guarantee that you won’t get cancer. They just
reduce the risk. And, since cancer treatment is still in its infancy, it makes more sense to take the easy
steps that prevent the development of cancer than rely on traumatic cancer treatment options.
Wo r k b o o k
Lesson 5.4
MC Questions:
What do I do if my cancer is incurable?
Surgery, radiation, and chemotherapy are performed with the intention of producing cancer remission,
and because of this, they are commonly called curative treatment. If cancer is not identified until it is
5. Which of the following is a significant
way to prevent the development of
cancer? (Circle all correct.)
aa. Smoking low-tar cigarettes.
bb. Vaccination against H. pylori.
cc. Avoiding tanning beds.
dd. Regular exercise.
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late stage, it is very difficult to fully treat the disease, and at this point curing the cancer is unlikely. In
these instances, doctors recommend a shift in treatment strategy from curative treatment to palliative
treatment, or treatment that emphasizes a reduction of symptoms rather than focusing on curing disease.
DEFINITIONS OF TERMS
Bereavement care – the type of
care that provides psychological
support for friends, family and
loved ones who have lost someone to disease.
Figure 3: As individuals live with cancer progressing in severity, the
focus of treatment shifts from curative care to palliative care. Once the
disease has become so severe that full time medical care is necessary to
relieve symptoms, hospice care is recommended. After death, bereavement
care is recommended for friends and families of the patient to help deal
with psychological stress of losing a loved one.
Palliative treatment is not dissimilar from curative treatment, as surgery, radiation, and chemotherapy
are still offered, but not so aggressively as to cure the disease. In the case of palliative treatment, just
enough treatment is offered to relieve the symptoms of the patient. If the cancer continues to worsen in
disease severity and full-time medical care is necessary, it is recommended that patients enter hospice
care. Hospices are homes for individuals with significant medical needs where medical support is
readily available, but is intended for people with late stage disease. Hospice care has been shown to
be much cheaper than hospitalization, but also has been shown to extend life by 3 months more than
hospitalization.
Wo r k b o o k
Lesson 5.4
Once a patient passes away from cancer, it is important to provide support to the family and friends of
the patient. This is called bereavement care, which provides psychological support for those who lost a
loved one. The view of cancer treatment focusing on palliative, hospice, and bereavement care treats a
patient more as a person rather than just focusing on treating the cancer. One of the hardest aspects to
consider is the death of a loved one, and this holistic approach has been shown to not only increase the
life-span of individuals with cancer, but allows patients to make their own choices on how they should die.
MC Questions:
6. Which of the following is an outcome
of palliative treatment? (Circle all
correct.)
aa. Improvement in mental health.
bb. Reduction of tumor size.
cc. Remission of cancer.
dd. Reduction of pain.
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7. Which of the following treatments
are considered most useful for
patients with late-stage cancer?
(Circle all correct.)
aa. Bereavement care.
bb. Curative care.
cc. Hospice care.
dd. Palliative care.
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STUDENT RESPONSES
What is one advantage and one disadvantage of trying to treat cancer using a holistic approach including palliative and
alternative treatments?
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Wo r k b o o k
Lesson 5.4
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173
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.4
DEFINITION
Alternative treatment
Any treatment that is not a mainstream treatment to cancer (i.e. not surgery, radiation, chemotherapy) that is
used instead of a mainstream treatment.
Anti-angiogenic
compound
Any chemical that inhibits the growth of blood vessels.
Antioxidant
A molecule that inhibits the activity of reactive oxygen species to damage DNA.
Bereavement care
The type of care that provides psychological support for friends, family and loved ones who have lost
someone to disease.
Complementary
treatment
Any treatment that is not a mainstream treatment to cancer (i.e. not surgery, radiation, chemotherapy) that is
used along with a mainstream treatment.
Conventional treatment
Any treatment typically used by medical professionals to treat cancer (i.e. surgery, radiation, and /or
chemotherapy).
Curative treatment
Any type of medical care given where a cure to disease is considered an achievable goal.
Hospice
A program /shelter that provides care to decrease pain and symptoms for patients as well as addressing
emotional and spiritual needs of the patient.
Intervention study
A study where one group is given a treatment to evaluate the effect of that treatment on people.
Palliative treatment
Treatment for a disease that is considered uncurable where the goal is to reduce symptoms and decrease
pain and stress associated with disease.
Relapse
The return of symptoms of cancer following a period of being disease-free.
Remission
The reduction of cancer symptoms, often considered being “cancer-free”.
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LESSON 5.5 WORKBOOK
How will cancer be treated in the
21st century?
DEFINITIONS OF TERMS
Driver mutation – a mutation
in a proto-oncogene or tumor
suppressor gene that drives the
transformation of a normal cell
into a malignant cancer cell.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.5
We now understand that how cancer progresses and whether it responds to
chemotherapy is a product of the gene mutations it accumulates. Yet none of the
current treatment options (surgery, radiation, and chemotherapy) target cancer
cells based upon the types of mutations the cells have acquired. This lesson
focuses on the future of cancer treatment and in particular how the genetic
sequences of tumors can be used to determine which therapies will be effective
to treat individual cancers. A more personalized approach to treatment should be
more successful than the current ‘one size fits all’ treatments.
MC Questions:
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Current cancer treatment is a relic of the past
The past few lessons have described the commonly used conventional approaches to cancer treatment.
All of them — surgery, chemotherapy, and radiation therapy — focus on killing cells on the basis of their
location or their proliferation rate. Even in the 21st century cancer treatments that address the underlying
cause of cancer — specific DNA mutations — or use other approaches to killing cancer cells, such as
activating the immune system, are largely experimental.
One element crucial to cancer progression that has only recently been appreciated is the so-called driver
mutations. These mutations to specific parts of specific proteins allow cells to acquire specific traits useful
to take advantage of selection pressure that will kill unprepared cells. If a treatment like chemotherapy kills
rapidly dividing cells randomly then any cell surviving the treatment that has already acquired the ability to
form secondary tumors will have a selective advantage. The presence of driver mutations explains why
many cancers relapse after chemotherapy. The future of cancer treatment lies in the ability to selectively
kill cells that have acquired driver mutations. We are closer now than ever to this goal, thanks to advances
in DNA sequencing.
1. What is the biggest problem with
current treatments for cancer?
aa. They are very expensive;
bb. They are less effective for
metastatic cells;
cc. They do not kill slow-growing
cells;
dd. They cannot kill cells that have
driver mutations.
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MC Questions:
Understanding cancer through deep sequencing
DEFINITIONS OF TERMS
Deep sequencing – a type of
DNA sequencing that uses computers to assemble of small DNA
sequences into a much longer
sequence, such as a genome.
Reference DNA – the DNA
sequence that is assembled
through the sequencing process.
Depth of Coverage – the number of sequence fragments that
overlap a given nucleotide during
a sequencing process
Wo r k b o o k
Lesson 5.5
Figure 1: Deep sequencing uses millions of short DNA sequences to assemble
much larger sequences, called the reference DNA, like as the genome. The short
regions of DNA are produced randomly and often overlap. Areas where many
sequences overlap have good coverage, while areas were few sequences overlap have
‘poor coverage’. Depth of coverage refers to how many times a single nucleotide is
represented in individual segments.
In 1987 a group of scientists proposed to collaborate to determine the exact sequence of nucleotides in
the entire human genome. These days, when we can find out our own genome sequences for only about
$1000 it is difficult to grasp how audacious the idea was at the time, and the technological advances
required for it to succeed. In 2001 the first draft of the genome sequence of one anonymous DNA donor
was published. (That donor is now known to be the famous biotechnologist Craig Venter). The human
genome-sequencing project would not have been possible without a number of new techniques that were
invented to sequence DNA faster and more efficiently. One of these techniques that has the potential to
revolutionize cancer treatment is called deep sequencing.
When the genome-sequencing project was begun, the only way to determine how nucleotides are
arranged in the genome was to chop up the DNA into segments 700-1000 bases in length and sequence
the segments individually. These sequences were then stitched together to build a reference DNA
sequence for the full genome. The method relied on specific enzymes that cut up the DNA at certain
points, and so it was effective only in areas where many of those enzymes could cut, so that there was
good overlap between segments (see Figure 1). But the enzymes didn’t work well in some areas of the
genome, which remained poorly sequenced for years. The development of more advanced computers that could handle large amounts of sequencing information at once changed the approach. Now
specific enzymes were not needed to cut the DNA. Instead it could be physically fractured into much
smaller pieces only 50-100 nucleotides long. The computers could then assemble millions of these
short sequences together to build a reference DNA sequence that covered the whole genome. The new
method, which randomly generates overlapping sequences increases the depth of coverage of the DNA
(see Figure 1) which is why it is called ‘deep’ sequencing.
2. What is deep sequencing?
aa. A type of sequencing of cells
deep within a tumor;
bb. A sequencing assembly using
DNA fragments of 50-100 bases;
cc. A sequencing assembly using
DNA fragments of 700-1000
bases;
dd. A type of sequencing of large
stretches of DNA.
3. What is the difference between good
coverage and poor coverage?
aa. Number of segments that cover
a given DNA nucleotide;
bb. Number of sequences that are
accurate for a segment of DNA;
cc. Number of DNA segments that
are covered by sequencing;
dd. None of the above.
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DEFINITIONS OF TERMS
The Cancer Genome Atlas
(TCGA) – a project to sequence
the genomes of many different
cancers to identify the types of
mutations that develop.
Transcriptome – the set of all
the messenger RNA molecules
made in a cell.
Epigenetics – the study of how
modifications to the DNA that do
not affect DNA sequence affect
gene expression.
Epigenome – a record of all of
the chemical changes of histones
and DNA and where these
changes are present along the
genome
Germline mutation – any
detectable mutation or variation
of DNA present within germ cells.
Somatic mutation – a change in
DNA sequence of a somatic cell.
Wo r k b o o k
Lesson 5.5
As the computers that permitted deep sequencing became faster and more efficient the time and cost to
sequence an entire genome fell from the 11 years and $3 billion dollars it originally cost to sequence Craig
Venter’s DNA to a few weeks and merely $1000 (as of this writing in late 2014). As the cost of genetic
sequencing has gone down, it has made sense to expand our efforts away from understanding the
healthy genome to include understanding the genome in disease. The US government has funded a new
project to understand the genetic origins of cancer called The Cancer Genome Atlas (TCGA). The goal
of this project is to sequence the genome of clinically important cancers including brain, bladder, breast,
colorectal, head and neck, kidney, leukemia, melanoma, prostate, stomach, and thyroid cancers and then
to map the types of genetic changes that occur in various types of cancers thereby making an ‘atlas’ of
key mutations.
But as we have learned, the DNA sequence of the genome only provides partial information – it is more
important to know what proteins are being expressed in cancer cells and how mutations might have
changed their functions. Realizing this, TCGA also plans to sequence the full repertoire of the RNA
transcripts produced in cancer cells that will be translated into proteins. This is called the transcriptome
map. Sequencing and then mapping the RNA Transcriptome sequencing should be especially useful for
identifying which RNA splicing variants are only produced in certain cancers or for identifying novel genes
expressed in cancer because of gene fusion events.
Another area we have learned about
that we expect will become increasingly
important in expanding our understanding
of how cancer progresses lies in the field of
epigenetics. Remembering back to Unit 2,
epigenetics studies how DNA structure can
be modified to control how tightly it is folded
and hence when a gene will be expressed.
The importance of epigenetics is that
even though it doesn’t change a gene’s
sequence, its effects can be passed down
Figure 2: Webpage for the Cancer Genome
from generation to generation. We have
Atlas (http://cancergenome.nih.gov/ ) holds
very little understanding of how epigenetics
genome, transcriptome, and epigenome data
might affect cancer. The third part of the
for several types of cancers of several organs.
TCGA project is therefore to create an
epigenome map to determine which regions
of DNA structure are epigenetically modified
in different cancers. This knowledge may provide important information about cancer inheritance that
doesn’t depend on modifications to actual genome structure.
MC Questions:
4. True or False: The Cancer Genome
Atlas will examine the sequence of
multiple different types of cancers to
map common genetic changes.
aa. True.
bb. False.
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5. Which of the following is information
that will be acquired by the cancer
genome atlas? (Circle all correct.)
aa. Genome of cancers.
bb. mRNAs of cancers.
cc. Histones acetylated in cancers.
dd. Proteins made in cancer.
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DNA sequencing and assessing cancer risk
In Unit 3 we learned about the difference between germline and somatic mutations. Germline mutations
occur in our germ cells (i.e. sperm cells for men, and egg cells for women), while somatic mutations
occur in any other cell in our body. We learned that germline mutations can be inherited, whereas somatic
mutations cannot. Germline mutations can be used to compare one person’s DNA to another, and, in
comparison with incidences of cancer, to assess which mutations may increase an individual’s risk for
developing incidences of cancer.
DEFINITIONS OF TERMS
Genetic screens – a type of
screen to identifies specific types
of mutations that may predispose
for cancer risk.
Prophylactic mastectomy
– surgery to remove one or both
breasts in order to reduce the risk
of developing breast cancer.
Wo r k b o o k
Lesson 5.5
Two well-known types of germline mutations that have definitively been associated with increased risk
of cancer are to the BRCA1 and BRCA2 tumor suppressor genes. Mutations to BRCA1 and BRCA2 are
most commonly associated with an increased risk of breast and ovarian cancer, but are also associated
with risk for colon, prostate, and pancreatic cancers. Other notable germline mutations linked to development of cancer include the Rb mutations that are associated with retinoblastoma (cancer of the retina)
and leukemia, and the p53 mutations that are associated with sarcomas, breast cancer, brain cancer, and
leukemia, as well as many other types of cancer.
The technology to perform genetic screens for germline mutations is readily available, people with family
histories of these types of cancer are recommended to be screened. In some cases the knowledge
gained from a positive screen can be used to prevent the cancers occurring. For example, the actress
Angelina Jolie recently announced that based on a family history of breast and ovarian cancer (her
mother died from ovarian cancer at a relatively young
age) she had been screened for BRCA1 and BRCA2
mutations. Based on a positive results she had undergone
a prophylactic mastectomy to remove both her breasts
even though she had not been diagnosed with cancer. Jolie
knew that the type of BRCA1 mutations she carried meant
that this surgery decreased her risk of breast cancer by
87%. However not all BRCA1 mutations confer the same
risk, and because of this prophylactic surgery is not the
answer for all people with BRCA1 or BRCA2 mutations. On
the other hand prophylactic breast surgery is not enough for
Figure 3: Angelina Jolie’s
women with the types of BRCA1 and BRCA2 mutations that
mutations in the BRCA 1
also significantly increase their risk of ovarian cancer. These
gene led to a prophylactic
women may also need to consider prophylactic removal of
mastectomy to reduce the risk
their ovaries. The ability to consider different options on a
of developing breast cancer.
case-by-case basis is an example of personalized medicine.
MC Questions:
6. True or False: Presence of BRCA1
is associated with increased risk of
breast and ovarian cancer.
aa. True.
bb. False.
7. What should decisions for cancer
treatment following a genetic screen
take into account? (Circle all correct.)
aa. An accurate assessment of the
risk of developing cancer.
bb. An accurate assessment of how
the treatment may affect the risk.
cc. An accurate assessment of the
dangers of the treatment relative
to the risk.
dd. All of the above.
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However it is important to evaluate the options carefully with an understanding of what the risk means.
Undergoing prophylactic surgery when the risk does not warrant it is another example of overtreatment.
Only 5-10% of all cancers have been attributed to inheritance of germline mutations to DNA. More may
be inherited via epigenetic modifications, as we discussed above, but we have little understanding of
epigenetic factors at present. The remainder of cancers appear to arise spontaneously in somatic cells.
To develop treatments for these cancers we will need to understand how different cells acquire the mutations that drive them towards becoming malignant.
DEFINITIONS OF TERMS
Personalized medicine – a type
of treatment plan that involves
customization of therapy to
specific cancers.
DNA sequencing of cancers: personalized treatment
As genetic sequencing becomes cheaper and more available, information about which mutations are key
drivers in cancer progression is becoming much clearer, and this allows us to design a logical strategy for
treatment rather than the non-specific ‘slash, burn and poison’ approach we have been using.
■■ When and how driver mutations are acquired may be more important than the tissue the cancer
develops in: For example if a lung cancer and a pancreatic cancer have the same mutations it
makes more sense to treat them both with the same drug that inhibits the driver’s activity than to
treat them with different drugs that were developed without taking into consideration how the cells
are abnormal.
■■ It is important to understand when metastasis occurs. If certain driver mutation are associated with
metastasis it makes more sense to include a treatment (like chemotherapy) that can kill metastatic
cells early in the treatment, rather than just removing the primary tumor.
■■ Tumors acquire mutations randomly so we need to be careful of selective pressures allow a resistant
population to persist even if most cells in the tumor are killed. We need to be able to kill that population too.
Wo r k b o o k
Lesson 5.5
The understanding, that each tumor has its own individual characteristics has given rise to the notion of
personalized medicine. Personalized medicine will take into account any germline mutations (genetic
and epigenetic) as well as the somatic mutations within a cancer, as well as the gene expression within
the tumor to design a treatment plan for that specific individual. This treatment may involve harnessing
the body’s own ability to fight disease via the immune system. The treatment focus has now shifted from
finding the cure for cancer to finding the unique cure for each unique cancer. We are within reach of finally
being able to treat cancer as a disease of evolution. This is the future of cancer treatment in the 21st
century, and the final battle in the war on cancer.
MC Questions:
8. What major advance may be crucial
to the development of personalized
medicine for treating cancer in the
21st century? (Circle all correct.)
aa. Combinatorial chemotherapy.
bb. Deep Sequencing.
cc. Radiation therapy.
dd. The Cancer Genome Atlas.
9. Which of the following would be
taken into account when designing
a personalized medicine treatment?
(Circle all correct.)
aa. That person’s genomic
sequence.
bb. That person’s cancer DNA
sequence.
cc. That person’s transcriptome.
dd. That person’s cancer
transcriptome.
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STUDENT RESPONSES
Identify three challenges in treating cancer that current treatments do not address and explain how personalized medicine
could be used to address them.
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Wo r k b o o k
Lesson 5.5
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180
TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.5
DEFINITION
Deep sequencing
A type of DNA sequencing that uses computers to assemble of small DNA sequences into a much longer
sequence, such as a genome.
Depth of Coverage
The number of sequence fragments that overlap a given nucleotide during a sequencing process
Driver mutation
A mutation in a proto-oncogene or tumor suppressor gene that drives the transformation of a normal cell into
a malignant cancer cell.
Epigenetics
The study of how modifications to the DNA that do not affect DNA sequence affect gene expression.
Epigenome A record of all of the chemical changes of histones and DNA and where these changes are present along
the genome
Genetic screens
A type of screen to identifies specific types of mutations that may predispose for cancer risk.
Germline mutation
Any detectable mutation or variation of DNA present within germ cells.
Personalized medicine
A type of treatment plan that involves customization of therapy to specific cancers.
Prophylactic mastectomy
Surgery to remove one or both breasts in order to reduce the risk of developing breast cancer.
Reference DNA
The DNA sequence that is assembled through the sequencing process.
Somatic mutation
A change in DNA sequence of a somatic cell.
The Cancer Genome
Atlas (TCGA)
A project to sequence the genomes of many different cancers to identify the types of mutations that develop.
Transcriptome
The set of all the messenger RNA molecules made in a cell.
181
LESSON 5.6 WORKBOOK
So what about the 'War on
Cancer'?
This module has provided a broad perspective to cancer as a disease, switching
focus among the DNA, cellular, organ, and systemic levels. As described in Unit
1, our understanding of cancer has changed over time, and will likely continue to
change as we learn more about the disease itself. This lesson is intended to take
a step back and examine everything we know about cancer currently, to gain
perspective on where we have come over the last several year, and where we still
need to go.
The ‘War on Cancer’
Wo r k b o o k
Lesson 5.6
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1. 1. What was the first organization to
begin the 'War on Cancer'?
aa. American Cancer Society.
bb. American Society for Control of
Cancer.
cc. Susan G. Komen Foundation.
dd. National Cancer Institute.
The popular media often describes people with cancer as ‘battling’,
‘fighting’, or ‘struggling with’ cancer. People that are in cancer remission are often described as ‘survivors’. Why is cancer in particular
treated so emotionally?
In the early 20th century, a cancer diagnosis was a death sentence.
Patients were usually in denial of their diagnosis or fearful of their
death. For this reason, doctors often did not tell their patients
they had cancer, nor did patients tell their loved ones. Cancer was
rarely mentioned in public. Then in 1913, 10 doctors and 5 other
concerned citizens founded the American Society for the Control
of Cancer (ASCC) to raise awareness of cancer as a disease.
The ASCC believed that the best way to defeat cancer is through
education. They wrote articles in magazines and professional
journals to educate the public about cancer. In 1936, Marjorie G.
Illig, an ASCC volunteer went one stage further. She created a
MC Questions:
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Figure 1: Original poster
for the ASCC.
182
LESSON READINGS
legion of volunteers whose purpose was to wage ‘war on cancer’ The Women’s Field Army wore khaki
uniforms, complete with insignia of rank and achievement and went out into the streets to raise money
and educate the public about cancer. Within 2 years their numbers swelled from 15,000 to 150,000
members. The Women’s Field Army moved the ASCC, which was eventually renamed the American
Cancer Society (ACS), to the forefront of cancer charities. Funding education, prevention, and research
projects with the goal of defeating cancer by improving cancer prevention and treatment . It made a major
contribution to cancer education in 1971 when lobbied President Nixon to pass the National Cancer
Act, which established a ‘War on Cancer’. The Act expanded the National Cancer Institute (NCI) and
increased federal funding for cancer research. Since 1971 it has spent nearly $90 billion dollars on its goal
to cure cancer within 30 years.
Cancer advocacy: pros and cons
Other charitable organizations have since joined the ACS and
the government’s ‘War on Cancer’. Some, such as the Jimmy
Fund of the Dana Farber and St. Jude’s Children’s Research
Hospital have arisen from hospitals that focus on cancer care,
and raise money to support research into treatments. Others
such as the Susan G. Komen Foundation and Livestrong have
been formed by cancer patients, survivors or their families with
the goal of ‘raising cancer awareness’.
Figure 2: Breast cancer
awareness poster. Awareness
campaigns promote early
detection without educating
individuals on what cancer
diagnosis means – leading to overdiagnosis and
overtreatment.
While research into cancer biology, prevention and treatment
is concrete and has clear goals, the notion of raising cancer
‘awareness’ is rather more vague, and recently, patient
advocates and activists have called into question whether
encouraging the population to wear pink ribbons and buy pink
merchandise or to grow moustaches in ‘Movember’ raises
awareness effectively. At issue is these cancer charities’
focus on making early screening universally available. Cancer
charities cite the 5-year survival rates for breast cancer and prostate cancer, which are among the highest
for all forms of cancer within the US population, as evidence for the success of their approach. Yet activists are concerned that these numbers are misleading and serve to divert resources from more critical
problems in cancer treatment and care.
Wo r k b o o k
Lesson 5.6
We have learned that while mass screening can indeed dramatically increase the number of early stage
tumors and cancers that are detected, neither screening alone nor follow-up biopsies can accurately
predict which of these tumors will give rise to severe disease. Because of this we currently treat all of
MC Questions:
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2. What was the major goal of the ACS?
aa. Developing new therapies for
cancer treatment;
bb. Educating the public about
cancer;
cc. Increasing funding for research;
dd. Organizing boycotts of tobacco
companies.
3. What is Breast Cancer Awareness
Month hoping to achieve?
aa. Build support for women who
are terminally ill;
bb. Encourage more people to have
breast cancer screens;
cc. Educate people on the biology of
breast cancer;
dd. Inform people on the causes of
breast cancer.
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LESSON READINGS
breast tumors as though they will, which as we have learned leads to overtreatment that can be extremely problematic. In fact in cases, such as prostate cancer, where we now have a better handle on which
tumors will progress to severe disease, recommendations for screening have been significantly reduced.
Hence labeling those individuals who have been diagnosed with early stage tumors that would never
have progressed to severe disease as ‘survivors’ gives a misleading impression of the effectiveness of the
screen, since the principal thing they may have survived is the unnecessary treatment they have received
as a result of the screen. On the other hand these same screening programs are not effective in reducing
the death rate from fast-growing metastatic cancers, if the tumor has spread before the screen has detected it. Activists argue that resources would be more effectively used by figuring out how to tie screening
results to prediction of outcome at the individual level – which is the hope of personalized medicine as we
learned in the last lesson. Moreover patient advocates consider that labeling patients who would never
have developed serious disease as ‘survivors’ while labeling patients who cannot be helped ‘losers’ in the
war on cancer is divisive and counterproductive.
Few of the prominent cancer charities focus on
awareness of cancers that are still essentially death
sentences, such as lung, stomach, liver and pancreas.
In this case activists argue that even though we may not
yet have screens to detect early stage tumors or viable
treatment options awareness campaigns should prioritize
education into minimizing risk. For example, lung cancer
is one of the highest causes of death in the US population
and is most frequently associated with smoking. In
fact smoking is one of the leading causes of all forms
of cancer, and is estimated to be responsible for about
30% of all cancers, yet cancer organizations focus little
attention on raising awareness of the dangers of smoking,
and smoking prevention campaigns have declined in the
last several years
Wo r k b o o k
Lesson 5.6
Figure 3: Smoking is one of
the most preventable causes of
cancer. It is believed at around
30% of all cancers are caused by
smoking tobacco products.
We now understand that unbalanced diets and obesity are other major risk factors for cancer. We learned
in Unit 3 that not only does obesity give rise to chronic inflammation that in turn can promote cell transformation, but it also reduces the ability of the immune system to handle cancers. Knowing this it is particularly puzzling that cancer awareness organizations have actually promoted the consumption of unhealthy
foods in order to raise money. For instance in a campaign to raise money for breast cancer awareness,
the Susan G. Komen Foundation partnered with KFC so that KFC would donate 50 cents for every bucket
of fried chicken it sold. Fried chicken, particularly from fast food restaurants like KFC, is generally high in
the calories fat and salt known to promote risk for obesity and potentially cancer. Once the media began
MC Questions:
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4. Which of the following would be a
useful awareness program from a
cancer charity? (Circle all correct)
aa. Advertisements encouraging
people to stop smoking.
bb. Partnership with McDonalds to
sell fried chicken to raise money
for research.
cc. Labels on foods that contribute
to obesity.
dd. Education materials explaining
what mammogram diagnoses
mean.
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LESSON READINGS
reporting on this contradiction the Susan G. Komen foundation cut its ties with KFC, but the event raised
questions about the extent to which other corporations were using connections to the cancer awareness
promotions run by charities like Susan G. Komen, to deflect attention from their involvement in increasing
the risk for cancer.
Defeating cancer
In the 40 years since the passage of the National Cancer
Act that started the ‘War on Cancer’ it is estimated
that $90 billion has been spent in the US on research
and treatment of cancer. Yet, major questions about
cancer – what causes it and how can we predict
whether a cancer will spread and cause disease – not
only remain unanswered but are a minor target of our
research dollars: It is estimated that of the $2 billion that
the ACS and NCI spent last year on the war on cancer
only ~$300 million was spent on research that focuses
on metastasis. Likewise only $233 million is spent on
education on cancer prevention. Activists ask whether
patient advocates are dictating where money is spent and
impeding progress.
Figure 4: The KFC Buckets
For The Cure partnership with
Susan G. Komen was criticized
by many patient advocates
for raising money for cancer
research and awareness while
also promoting obesity and
increasing cancer risk.
Will we ever be able to prevent cancer. Unlikely. Random
DNA mutations accumulate no matter what we do so
preventing the random DNA mutations that mutate protooncogenes or tumor suppressor genes to drive cell transformation is an impossible task. Accumulation
of random mutations increases with age, which is why cancer is more frequent in the elderly. So while
we cannot prevent all random DNA mutations, it is likely we will be able to reduce the extent to which
they occur by minimizing exposure to environmental carcinogens particularly cigarette smoke, diet, and
pathogens that increase the frequency of mutation.
Wo r k b o o k
Lesson 5.6
Will we ever be able to cure cancer? Research funded by the ‘War on Cancer’ has taught us so much
about how cells behave, much of it so completely unexpected that it is not surprising we have not yet
solved the problem. But as we learn more we move further towards treating individuals diagnosed with
cancer so they can lead long healthy lives. While cancer may be inevitable for the very old, we may
indeed be able to eradicate it in the young. Understanding metastasis is one key, another is the choices
we ourselves make to reduce risk.
Notes:
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185
STUDENT RESPONSES
Why have concerns been expressed about cancer awareness campaigns?
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Lesson 5.6
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The Great Diseases Project
Department of Developmental, Molecular and Chemical Biology
150 Harrison Ave., Boston, MA 02111