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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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6. Which of the following prevents cells
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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Remember to identify your
sources
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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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