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Chapter 24
Cancer Cells
Lectures by
Kathleen Fitzpatrick
Simon Fraser University
© 2012 Pearson Education, Inc.
Cancer Cells
• Cancer, the second leading cause of death, is an
example of a disease that arises from abnormalities
in cell function
• Gene mutations and changes in gene expression
play a central role in development of cancer
• Investigating the biology of cancer cells has
deepened our understanding of normal cells
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Uncontrolled Cell Proliferation and
Survival
• The term cancer was coined to describe diseases
in which tissues grow and spread abnormally
• Cancers are grouped into categories depending on
the cell type involved
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Types of cancers
• Carcinomas arise from epithelial cells that cover
external and internal body surfaces (e.g., lung,
breast, and colon cancer)
• Sarcomas develop from supporting tissues such
as bone, cartilage, fat, and muscle
• Lymphomas and leukemias arise from cells of
lymphatic and blood origin, respectively
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Tumors Arise When the Balance
Between Cell Division and Cell
Differentiation or Death Is Disrupted
• A cancer is an abnormal type of tissue growth, in
which some cells divide and accumulate in an
uncontrolled, relatively autonomous way
• The resulting mass of growing tissue is called a
tumor (or neoplasm)
• Tumors lack the normal balance between cell
division and differentiation or death
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Differentiation of skin cell
• Each time a basal cell divides, one of the two cells
produced loses the ability to divide, and undergoes
differentiation as it moves toward the skin surface
• During differentiation it flattens out and begins to
make keratin
• Eventually the cell dies and is shed from the skin
surface
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Balance of cells in the basal layer
• Whenever a cell divides in the basal layer, one cell
differentiates and the other remains in the basal
layer and retains its ability to divide
• This arrangement ensures that there is no increase
in the number of dividing cells
• In tumors this finely balanced arrangement is
disrupted, so that some divisions give rise to cells
that both continue to divide
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Figure 24-1
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Benign and malignant tumors
• As the abnormal dividing cells accumulate, the
normal organization and function of the tissue is
disrupted
• Benign tumors grow in a confined local area and
are rarely dangerous; malignant tumors can
invade surrounding tissues, and spread throughout
the body
• Cancer refers to any malignant tumor
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Cancer Cell Proliferation Is
Anchorage-Independent and
Insensitive to Population Density
• Cancer cells that are injected into nude mice (which
have no functional immune system) will proliferate
and form tumors; normal human cells will not grow
• Normal cells won’t grow well in culture without solid
surface to attach to
• Cancer cells grow in culture with or without a solid
support
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Figure 24-2
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Cancer cell proliferation (continued)
• Cancer cells exhibit anchorage-independent
growth
• Most normal cells anchor to the substrate through
integrins
• If integrins are inhibited, the cells lose the ability to
divide and self-destruct by apoptosis
• Cancer cells circumvent this process
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Cancer cell proliferation (continued)
• Normal cells grown in culture divide until the
surface of the vessel is covered by a single layer
of cells (the monolayer stage)
• This is called density-dependent inhibition of
growth
• Cancer cells show reduced sensitivity to densitydependent growth
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Cancer Cells Are Immortalized by
Mechanisms That Maintain Telomere
Length
• Normal cells in culture divide a limited number of
times
• They stop dividing, undergo degenerative changes,
and may die
• Cancer cells under similar conditions exhibit no
limitation, continuing to divide—e.g., HeLa cells,
first isolated in 1951, are still growing in culture
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Telomeric sequences
• Telomeric sequences are lost from the tips of
each chromosome with every DNA replication
• If a normal cell divides too many times, the
telomeres become too short to protect the ends of
the chromosomes and a pathway to halt cell
division is initiated
• Cancer cells express telomerase, an enzyme that
maintains telomere length
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Defects in Signaling Pathways, Cell
Cycle Controls, and Apoptosis
Contribute to Uncontrolled Proliferation
• Proliferation is regulated by growth factors that
bind cell surface receptors and activate signaling
pathways in the target cells
• Normal cells do not divide unless stimulated by
the proper signals
• Cancer cells alter signaling pathways to create a
constant signal to divide
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Disruptions in cell cycle control
• The commitment to proceed through the cell cycle
is made at the restriction point (G1 to S
progression)
• Under suboptimal conditions, normal cells arrest at
the restriction point (cease dividing)
• Under comparable conditions, cancer cells continue
to divide due to defects in cell cycle controls
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Apoptosis
• Cell death is controlled mainly by pathways that
trigger apoptosis to remove unnecessary or
defective cells
• Cancer cells are defective and unnecessary but
elude apoptosis by blocking the pathway
• In some cancers uncontrolled growth arises more
from failure to undergo apoptosis than from
increased cell division
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How Cancers Spread
• What makes cancer dangerous is its uncontrolled
proliferation combined with the ability to spread
throughout the body
• This makes it impossible to remove surgically
• Most cancer deaths (~90%) are caused by the
spread of cancer rather than the primary tumor
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Angiogenesis Is Required for
Tumors to Grow Beyond a Few
Millimeters in Diameter
• In 1971 Folkman proposed that tumors release
signaling molecules that trigger angiogenesis
(growth of blood vessels)
• These blood vessels were required for the tumors
to grow beyond a tiny localized clump of cells
• The idea emerged from studies on cancer cells
grown under artificial conditions
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Experiments with cancer cells
• A normal thyroid gland was grown in a glass
chamber
• A small number of cancer cells was injected into
the thyroid, and a nutrient solution was provided to
keep the organ alive
• In these conditions, the cancer cells divided until
the tumor reached 1–2 mm across, then stopped
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Figure 24-3A
© 2012 Pearson Education, Inc.
Experiments with cancer cells (continued)
• When the tumor cells were removed from the gland
and injected into animals, the cells resumed
dividing and formed large tumors
• Microscopic examination showed that the tiny
tumors in the thyroid had not been able to connect
to the blood vessels
• However, the tumors in the animals had done so,
and grew to enormous size as a result
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Figure 24-3B
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Video: Tumor Angiogenesis in a Living Mouse
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Blood Vessel Growth Is Controlled by
a Balance Between Angiogenesis
Activators and Inhibitors
• In key experiments cancer cells were placed into
chambers with pores so tiny that cells could not
pass through
• These were implanted into animals, and the growth
of new capillaries in the tissues around the implant
was observed
• Cancer cells produce molecules that activate
angiogenesis
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Angiogenesis-activating molecules
• Factors promoting angiogenesis are proteins called
vascular endothelial growth factor (VEGF) and
fibroblast growth factor (FGF)
• When these proteins are released into the
surrounding tissue, they bind receptors on the
surface of endothelial cells lining blood vessels
• The binding activates a signaling pathway that
causes endothelial cells to divide
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Angiogenesis (continued)
• Stimulated endothelial cells secrete proteindegrading enzymes called matrix
metalloproteinases (MMPs)
• MMPs break down the extracellular matrix,
permitting the endothelial cells to migrate into the
surrounding tissues, becoming organized into new
blood vessels
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Angiogenesis (continued)
• More than a dozen naturally occurring inhibitors of
angiogenesis have been discovered, including
angiostatin, endostatin, and thrombospondin
• When tumors secrete angiogenesis activators,
there is usually a simultaneous decrease in
production of angiogenesis inhibitors
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Cancer Cells Spread by Invasion
and Metastasis
• The ability of cancer cells to spread depends on
two different mechanisms
– Invasion refers to the direct migration and
penetration of cancer cells into neighboring tissues
– Metastasis involves ability of cancer cells to enter
the bloodstream and travel to distant sites
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Metastasis
• New tumors formed some distance from the
primary tumor are called metastases
• The ability of a tumor to metastasize depends on a
cascade of events beginning with angiogenesis
• The events following angiogenesis can be grouped
into three main steps
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Steps of metastasis
• 1. Cancer cells invade surrounding tissues and
gain access to the bloodstream
• 2. Cancer cells are transported throughout the
body via the circulatory system
• 3. Cancer cells leave the circulatory system and
enter various organs, where they establish new
metastases
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Figure 24-4
© 2012 Pearson Education, Inc.
Changes in Cell Adhesion, Motility,
and Protease Production Allow Cancer
Cells to Invade Surrounding Tissues
and Vessels
•
The first step in metastasis is the invasion of
surrounding tissues and vessels
•
Benign tumors and normal cells remain together
where they are formed
•
Cancer cells are able to leave their original location
through several mechanisms, the first of which
involves loss of cell adhesion
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Cell adhesion
• Cell surface proteins such as E-cadherin, which
cause cells to adhere to one another, are often
missing or defective in cancer cells
• Highly invasive cancer cells usually have less
E-cadherin than do normal cells; restoring
E-cadherin to cancer cells inhibits their
invasiveness
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Cell motility
• Cancer cells have increased motility, stimulated by
signaling molecules from the surrounding tissues,
or from the cancer cells themselves
• Some molecules act as chemoattractants, guiding
signals that attract cancer cells
• Activation of Rho family GTPases plays a central
role in stimulating motility
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Crossing the basal lamina
• Cancer cells produce proteases that degrade
structures such as the basal lamina, a dense layer
that separates epithelial cells from underlying
tissues
• E.g. plasminogen activator converts plasminogen
into the active plasmin
• Plasmin degrades components of the basal lamina
and activates proteases from host cells that do the
same
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Gaining entry into the circulatory system
• Proteases allow cancer cells to penetrate the
basal lamina and facilitate migration by degrading
the ECM of underlying tissues
• Proteases also digest holes in the lamina
surrounding lymphatic or blood vessels, gaining
entry into the circulatory system
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Relatively Few Cancer Cells Survive
the Voyage Through the Bloodstream
• Once in the bloodstream, cancer cells are
transported through the body
• If cancer cells penetrate lymphatic vessels, they
are first transported to lymph nodes, where they
can become lodged and grow
• The lymphatic system is connected to the blood
system, so such cells can eventually reach the
bloodstream
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Cancer cells in the bloodstream
• The bloodstream is relatively inhospitable to
cancer cells; fewer than one in one thousand
survives to reach a potential site of metastasis
• Whether the successful metastases are formed
through random sampling or from cells that are
particularly well suited for metastasis has been
addressed experimentally
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The experiment
•
Mouse melanoma cells were injected into mice; a few
weeks later, metastases were found in the lungs
•
Cells from the lung metastases were isolated and
injected into mice, leading to production of more
metastases
•
Through repetition, cells were isolated that formed
many more metastases than the originals, suggesting
that the researchers had gradually selected the most
suitable cells
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Figure 24-5
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A further test
• Single cells from the primary melanoma of the
previous experiment were cultured separately
• Each formed a population of cells derived from the
original (clones)
• When injected into animals, each clone varied in
its ability to produce metastases, confirming that
different cells in a tumor have different abilities to
metastasize successfully
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Blood-Flow Patterns and OrganSpecific Factors Determine the Sites of
Metastases
•
Metastases form preferentially at certain locations
•
The specificity is related to blood-flow patterns; cancer
cells are most likely to lodge in tiny capillaries, from
which they enter the surrounding tissues
•
Thus the lungs are a common site of metastasis for
some cancers, and the liver is more common in the
case of stomach and colon cancer
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The affinity of cancer cells for certain
organs
• In 1889, Paget first proposed that circulating
cancer cells have an affinity for the environment
provided by particular organs
• This is called the “seed and soil” hypothesis
• Cancer cells are carried to a variety of organs by
the bloodstream but only some sites provide an
optimal environment for their growth
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Systematic analysis of sites of metastases
•
When the sites of metastasis are analyzed carefully,
blood flow patterns can explain the locations of the
metastases in about 2/3 of the cases
•
In the remaining cases, metastases occurred in
particular organs either less or more frequently than
expected
•
Interactions between the cancer cells and the
microenvironments of the organs are likely responsible
for this
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The Immune System Influences the
Growth and Spread of Cancer Cells
• The immune surveillance theory postulates that
immune destruction of cancer cells is common,
and cancer results from an occasional failure of
the immune system to destroy the aberrant cells
• Organ transplant patients, who take
immunosuppressive drugs, develop many cancers
at higher rates than normal
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Studies on immune system and cancer
• Rag2 mutant mice have no functional lymphocytes
and thus no immune response
• These mice exhibit increased rates of both
spontaneous and induced tumors
• These results indicate that the immune system
protects mice from developing cancer; AIDS
provides evidence regarding the immune system
and cancer in humans
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AIDS and cancer
• AIDS patients have severely decreased immune
function
• AIDS causes higher rates of a few types of cancer
but not the most common forms
• The human immune system may not be very
successful in defending against the most common
types of cancer
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Cancers can evade the immune system
• Tumors are heterogeneous populations of cells that
express different antigens
• Cells expressing antigens that elicit a strong
immune response will likely be attacked and
destroyed
• Cells producing fewer (or none) of these antigens
are more likely to survive; and some grow so fast
that the immune system cannot clear them all
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The Tumor Microenvironment
Influences Tumor Growth, Invasion,
and Metastases
•
The tumor microenvironment includes various kinds of
normal cells, extracellular molecules, and the
components of the extracellular matrix
•
Angiogenesis and motility are affected by both factors
secreted by tumor cells and those made by normal
cells in the surrounding tissues
•
The microenvironment may also contain cells and
molecules that hinder invasion and metastasis
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Hindering invasion and metastasis
• Normal cells of the immune system may attack
cancer cells
• Other cells in the microenvironment may produce
TGFb, a potent inhibitor of proliferation for many
types of cells
• Cancer cells may acquire mutations allowing them
to evade inhibition by TGFb, or may begin
secreting it, inhibiting growth of their neighbors
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What Causes Cancer?
• Cancers are commonly caused by environmental
agents and lifestyle factors
• Most of these act by triggering DNA mutations
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Epidemiological Data Have Allowed
Many Causes of Cancer to Be Identified
• Epidemiology investigates the frequency and
distribution of diseases in human populations
• Certain cancers are more frequent in different parts
of the world
• To determine whether the causes are hereditary or
environmental, scientists study rates of cancer in
people who have moved from one country to
another
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Environmental and lifestyle factors are
mainly responsible
• People who move to new countries experience the
same cancer rates as other inhabitants of the new
country
• This suggests that the most important factors in
rates and types of cancer are environmental and
lifestyle factors
• E.g. most people who develop lung cancer have a
history of smoking cigarettes
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Figure 24-6
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Smoking and cancer
• Heavier smokers develop lung cancer more
frequently than light smokers
• Long-term smokers develop lung cancer more
frequently than short-term smokers
• Lung cancer rates fall for smokers who have quit
smoking
• Smoking is linked to many other types of cancer
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Figure 24-6
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Many Chemicals Can Cause Cancer,
Often After Metabolic Activation in the
Liver
• Early observations of snuff users and chimney
sweeps suggested that exposure to certain
chemicals was associated with cancer
• The list of known and suspected carcinogens
(cancer-causing agents) includes hundreds of
chemicals
• These chemicals do not always cause cancer by
their own action, though
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Example: 2-naphthylamine
• 2-naphthylamine is a potent carcinogen that
causes bladder cancer
• Feeding it to lab animals induces a high rate of
bladder cancer, but implanting it directly into the
bladder does not
• When 2-naphthylamine passes through the liver, it
is metabolized into other chemicals that are the
actual causes of the cancer
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Precarcinogens
•
Many carcinogens share this need for metabolic
activation before they cause cancer
•
Substances like these are called precarcinogens, to
apply to any chemical that can cause cancer only after
it is metabolically activated
•
Precarcinogens are mainly activated by cytochrome
P450 family members, which oxidize drugs and
pollutants, usually to make them less toxic; in this
case, carcinogen activation occurs instead
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DNA Mutations Triggered by Chemical
Carcinogens Lead to Cancer
• The Ames test uses bacteria to test a chemical’s
mutagenic activity
• The bacteria used cannot synthesize histidine; they
are placed in a culture dish with a medium lacking
histidine and the chemical being tested
• If the chemical is mutagenic, it will trigger DNA
mutations, some of which will allow the bacteria to
grow in the absence of histidine
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Testing precarcinogens with the
Ames test
• The Ames test includes a step in which the
chemical tested is incubated with a liver cell extract
to mimic carcinogenic activation
• The number of colonies that grow is a direct
measure of the mutagenic strength of a chemical
• Strong correlation is observed between a
chemical’s ability to cause mutations and to cause
cancer
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Figure 24-7
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Figure 24-7
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How carcinogens cause DNA damage
• Carcinogens inflict damage in several ways,
including
-
Disrupting base-pairing
Generating crosslinks between the strands
Creating chemical linkages between adjacent
bases
Chemically altering or removing individual bases
Causing breaks in the DNA strands
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Cancer Arises Through a Multistep
Process Involving Initiation,
Promotion, and Tumor Progression
• The development of cancer requires multiple steps
• Early evidence comes from studying the ability of
DMBA (dimethylbenz[a]anthracene) to cause
cancer in lab animals
• A single dose of DMBA rarely causes tumors to
develop
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Cancer develops through multiple steps
• A mouse that has had a single dose of DMBA and
is later treated with a substance that causes skin
irritation will develop cancer at the site of treatment
• The irritant used is croton oil, which is enriched in
phorbol esters
• DMBA and croton oil play different roles in cancer
development
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Figure 24-8
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Initiation and promotion
• DMBA can create a permanently altered state in
cells of the body; this initiation can persist for a
year or more after feeding animals the DMBA
• This state is based on production of DNA mutations
• Promotion is a gradual process requiring
prolonged or repeated exposure to agents such as
phorbol esters
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Promoting agents stimulate cell
proliferation
• Promoting agents (such as phorbol esters) can
stimulate cell proliferation
• Hormones and growth factors may also act as
tumor promoters if they act on a cell that has
already sustained an initiating mutation
• As cells proliferate, those with mutations causing
enhanced growth and invasiveness will be favored
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Figure 24-9, Steps 1 and 2
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Tumor progression
• Initiation and promotion are followed by tumor
progression, when tumor cell properties change
over time
• Tumors acquire more aberrant traits and become
more aggressive
• Cells exhibiting such traits are selectively favored
over their neighboring, normal cells
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Figure 24-9, Step 3
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Acquiring new traits
• New traits arise in tumor cells through additional
DNA mutations, following the original, initiating
mutation
• New traits can be acquired through epigenetic
mechanisms as well, the inhibition of gene
function without mutating the DNA sequence
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Ionizing and Ultraviolet Radiation
Also Cause DNA Mutations That
Lead to Cancer
• Shortly after the discovery of X-rays, it was
noticed that people working with X-rays
developed cancer at high rates
• Animal studies confirmed that X-rays create DNA
mutations and cause cancer in proportion to the
dose of radiation
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DNA damage
• X-rays and related forms of radiation are called
ionizing radiation; they remove electrons from
molecules and generate reactive ions that
damage DNA
• Ultraviolet radiation (UV) can also cause cancer by
causing formation of pyrimidine dimers – links
between adjacent pyrimidine bases
• If not repaired, mutations are created in the DNA
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p53
• p53 is known to be mutated in many cancers
• When the p53 gene in skin cancer cells is
examined, mutations such as CC → TT are
observed, characteristic of UV-induced damage (a
UV “signature”)
• p53 mutations in other types of cancer do not have
this type of mutation
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Figure 24-10
© 2012 Pearson Education, Inc.
Viruses and Other Infectious Agents
Trigger Development of Some Cancers
• In 1911, Peyton Rous first demonstrated that
cancer can be caused by a virus
• The chickens he studied had sarcomas, cancers of
connective tissue
• He ground tumor tissue, and passed it through a
filter that even bacteria could not pass through; the
extract caused cancer when injected into healthy
animals
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Oncogenic viruses
• Rous concluded that the agent that caused the
cancer was smaller than a bacterial cell; it was the
first detected oncogenic (cancer-causing) virus
• Burkitt lymphoma was shown to be caused by the
Epstein-Barr virus (EBV) in the 1950s
• Since then dozens of viruses that cause cancer
have been identified
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Examples of oncogenic viruses
• Hepatitis B and C – liver cancers
• Human T-cell lymphotropic virus-1 (HTLV-1) – adult
T-cell leukemia
• Human papilloma virus (HPV) – uterine and
cervical cancers
• Vaccines against these viruses (hepatitis B and
HPV) can reduce the incidence of these cancers
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Figure 24-11
© 2012 Pearson Education, Inc.
Other oncogenic infectious agents
• Helicobactor pylori (H. pylori) – stomach cancer
-
H. pylori is associated with stomach ulcers;
antibiotics that kill H. pylori help prevent stomach
cancer
• Flatworm infections—bladder and bile duct
cancers
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Mechanism of action of infectious agents
• There are two main mechanisms of oncogenesis
• 1. The agents cause tissue destruction and
inflammation
-
Oxygen free radicals, produced in fighting the
infection, create DNA mutations
• 2. The stimulation of proliferation of infected cells
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Oncogenes and Tumor Suppressor
Genes
• DNA mutations in cancer originate in different ways
• However the mutations always affect genes that
control cell proliferation and survival
• There are two main classes: oncogenes and tumor
suppressor genes
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Oncogenes Are Genes Whose
Products Can Trigger the Development
of Cancer
• An oncogene is a gene whose presence can trigger
cancer; some are introduced by cancer-causing
viruses, others arise from mutation of normal genes
• The first oncogene discovered was in the Rous
sarcoma virus
• Viruses with defects in the src gene can infect cells
but don’t cause cancer
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Oncogenes in cancers not caused by
viruses
• DNA from human cancer cells was introduced into
cultured mouse 3T3 cells
• DNA was administered under conditions that
stimulate transfection – uptake of foreign DNA into
cells, and incorporation into chromosomes
• After transfection, some 3T3 cells proliferated
excessively
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Oncogenes in cancers not caused by
viruses
• The abnormal 3T3 cells were injected into mice,
which then developed cancer – suggesting that a
human gene taken up by the cells caused the
cancer
• This resulted in identification of RAS, the first
human oncogene identified of more than 200 now
known
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Single oncogenes are not sufficient to
cause cancer
• The RAS oncogene only caused cancer because
of a pre-existing cell cycle mutation in the 3T3 cells
• In normal cells, the RAS oncogene alone will not
cause cancer, but the RAS oncogene combined
with oncogenes that target the p53 pathway will
• Multiple mutations are usually required to convert a
normal cell into a cancer cell
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Proto-oncogenes Are Converted into
Oncogenes by Several Distinct
Mechanisms
• Oncogenes arise by mutation from normal cellular
genes called proto-oncogenes
• They are normal cellular genes that contribute to
the regulation of cell growth and survival
• When their structure or activity is disrupted by
mutation (through several mechanisms), the
mutant form of the gene can cause cancer
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1. Point Mutation
• The simplest mechanism for converting a protooncogene into an oncogene is a point mutation
• This is a single nucleotide substitution that causes
a single amino acid change in the protein product
• E.g., point mutations in RAS create abnormal,
hyperactive forms of the Ras protein that lead to
excessive cell proliferation
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2. Gene Amplification
• Gene amplification increases the number of copies
of a proto-oncogene
• This causes the protein product to be produced in
excess, although the protein produced is normal
• E.g. some breast and ovarian cancers have
amplified copies of the ERBB2 gene, which
encodes a growth factor receptor; multiple copies
lead to excessive cell proliferation
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Figure 24-12A, B
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3. Chromosomal Translocation
• In chromosomal translocation a part of one
chromosome is joined to another chromosome
• E.g., in Burkitt lymphoma, EBV stimulates cell
proliferation but cannot cause cancer by itself
• Cancer arises when a translocation involving
chromosomes 8 and 14 occurs in one of the
proliferating cells
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The translocation in Burkitt lymphoma
• The translocation in Burkitt lymphoma often moves
the MYC gene from chromosome 8 to a highly
active region of chromosome 14 coding for antibody
molecules
• This leads to overproduction of the Myc protein—a
transcription factor that stimulates cell proliferation
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Figure 24-13
© 2012 Pearson Education, Inc.
The Philadelphia chromosome
• The Philadelphia chromosome is a translocation
chromosome that involves chromosomes 9 and 22
and is associated with chronic myelogenous
leukemia
• The translocation creates an oncogene called
BCR-ABL, a fusion of two genes (BCR and ABL),
the oncogene produces a fusion protein that
functions abnormally
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Figure 24-12C
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4. Local DNA Rearrangements
• Local rearrangements alter base sequences of
proto-oncogenes by deletions, insertions,
inversions, or transpositions
• E.g., two genes, NTRK1 and TPM3, reside on the
same chromosome
• In some cancers a DNA inversion causes one end
of the TPM3 gene to fuse to the opposite end of the
NTRK1 gene
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Figure 24-12D
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The TRK oncogene
• The resulting gene is called the TRK oncogene,
which fuses the tyrosine kinase part of the
receptor (NTRK1) to a region of the tropomyosin
molecule
• This fusion protein creates a permanently
activated tyrosine kinase
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Figure 24-14
© 2012 Pearson Education, Inc.
5. Insertional Mutagenesis
• Retroviruses can sometimes cause cancer by
integrating their own genes into a host
chromosome in a region where a proto-oncogene
is located
• This is called insertional mutagenesis; the protooncogene is converted into an oncogene by
causing it to be overexpressed
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Figure 24-12E
© 2012 Pearson Education, Inc.
Most Oncogenes Code for Components
of Growth-Signaling Pathways
• More than 200 oncogenes have been identified, and
many of them encode proteins in one of six
categories
• Each of the six categories is related to steps in
growth-signaling pathways
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Table 24-1
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1. Growth Factors
• Normal cells will not divide unless they have been
stimulated by the appropriate growth factor
• But if a cell possesses an oncogene that produces
the growth factor, it can stimulate its own
proliferation
• The v-sis gene (found in the simian sarcoma virus)
encodes a mutant form of platelet-derived growth
factor (PDGF)
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PDGF
• When the virus infects a monkey cell that is normally
controlled by PDGF, the PDGF produced by v-sis
stimulates the cell’s proliferations
• A PDGF-related oncogene has also been detected
in some human sarcomas
• These have a translocation that joins part of the
PDGF gene to part of the collagen gene resulting in
uncontrolled production of PDGF
© 2012 Pearson Education, Inc.
2. Receptors
• Oncogenes sometimes code for mutant versions of
receptors with permanently activated tyrosine
kinase activity, even in the absence of a growth
factor
• E.g., the v-erb-b oncogene is found in a virus that
causes red blood cell cancer in chickens
• It produces an altered version of the epidermal
growth factor (EGF) receptor that remains
constitutively active
© 2012 Pearson Education, Inc.
Figure 24-15A, B
© 2012 Pearson Education, Inc.
Overproduction of receptors
• Other oncogenes produce normal receptors, but in
excessive quantities
• The presence of too many receptors causes a
magnified response to growth factor and hence
overproliferation
© 2012 Pearson Education, Inc.
3. Plasma Membrane GTP-Binding
Proteins
• Oncogenes coding for mutant Ras (plasma
membrane GTP-binding protein) are one of the
most common genetic abnormalities found in
human cancers
• The mutations that create RAS oncogenes are
usually point mutations that lead to hyperactive
Ras that remains in a permanently active state
© 2012 Pearson Education, Inc.
4. Nonreceptor Protein Kinases
• Protein phosphorylation is a common feature of
many growth-signaling pathways
• The enzymes that catalyze these intracellular
phosphorylations are nonreceptor protein
kinases
• E.g., in the Ras pathway, activated Ras
phosphorylates Raf protein kinase
© 2012 Pearson Education, Inc.
Nonreceptor protein kinases
• Several oncogenes code for protein kinases
involved in the phosphorylation cascade triggered
by Ras
• BRAF codes for a mutant Raf protein in a variety of
human cancers
• Oncogenes coding for nonreceptor protein kinases
in other pathways have also been identified
© 2012 Pearson Education, Inc.
5. Transcription Factors
• Receptor tyrosine kinase activation triggers changes
in transcription factors, altering gene expression
• Oncogenes that produce mutant forms or excessive
amounts of various transcription factors have been
detected in many types of cancers
• Among the most common are oncogenes coding for
Myc transcription factors that control genes involved
in survival and proliferation
© 2012 Pearson Education, Inc.
6. Cell Cycle and Apoptosis Regulators
• Transcription factors activate genes that code for
proteins controlling cell proliferation and survival
• The activated genes include those coding for
cyclins and cyclin-dependent kinases (Cdks) that
trigger passage through key steps of the cell cycle
• Several human oncogenes produce proteins of this
type; e.g., CDK4 is amplified in some sarcomas
and the cyclin gene, CYCD1, is commonly
amplified in breast cancers
© 2012 Pearson Education, Inc.
Inhibition of apoptosis
• Some oncogenes contribute to accumulation of
proliferating cells by inhibiting apoptosis
• One example involves the gene that encodes the
apoptosis-inhibiting protein Bcl-2; some cancers
are associated with translocations that result in
overproduction of Bcl-2
• MDM2, which codes for a protein that targets p53
for destruction can also cause failure of apoptosis
when it is amplified or overexpressed
© 2012 Pearson Education, Inc.
Tumor Suppressor Genes Are Genes
Whose Loss or Inactivation Leads to
Cancer
• The loss or inactivation of tumor suppressor genes can
also lead to cancer
• The normal function of such genes is to restrict cell
proliferation; the first understanding that such genes
exist came from cell fusion experiments
• Fusion of cancer cells with normal cells usually
produces hybrid cells that behave normally; providing
evidence that cells contain genes whose products can
suppress tumor growth
© 2012 Pearson Education, Inc.
Figure 24-16
© 2012 Pearson Education, Inc.
The hybrid cells don’t stay normal
• Over time, the hybrid cells can revert to malignant
uncontrolled growth
• Reversion to malignancy is associated with the loss
of certain chromosomes, suggesting that these
chromosomes had tumor suppressor genes
on them
• Identifying tumor suppressor genes has been
difficult
© 2012 Pearson Education, Inc.
Hereditary cancers
• One approach to identification of tumor suppressor
genes is through the study of families at high risk
for cancer
• About 10–20% of cancers can be traced to
inherited mutations
• Susceptibility to developing cancer can be
inherited; the susceptibility is related to defects in
tumor suppressor genes
© 2012 Pearson Education, Inc.
Hereditary cancers (continued)
• In hereditary cancers, one copy of a tumor
suppressor gene is mutated; if the wild-type copy
is also mutated, the cell can begin the progression
toward cancer
© 2012 Pearson Education, Inc.
Figure 24-17, Left
© 2012 Pearson Education, Inc.
The RB Tumor Suppressor Gene Was
Discovered by Studying Families with
Hereditary Retinoblastoma
•
In hereditary retinoblastoma, a rare eye cancer
develops in young children with a family history of the
disease
•
Children with this condition inherit a deletion in part of
chromosome 13; the deletion alone does not cause
cancer
•
However, during many cell divisions, a retinal cell may
occasionally acquire a mutation in the same region
© 2012 Pearson Education, Inc.
Identification of the RB gene
• The pattern of development of the disease
suggests that
-
1. Chromosome 13 contains a gene that normally
inhibits proliferation
-
2. Deletion or disruption of both copies must occur
before cancer develops
• The RB gene was identified as the missing gene
© 2012 Pearson Education, Inc.
Role of Rb
• The product of the RB gene, Rb protein controls
the G1 to S phase progression in the cell cycle
• Rb is part of a mechanism that prevents cells from
passing G1 unless an appropriate signal from a
growth factor is received
• Disrupting both copies of RB opens the door to
uncontrolled proliferation
© 2012 Pearson Education, Inc.
Rb in other cancers
• Mutations in the RB gene have been detected in
nonhereditary cancers as well
• The Rb protein is a target of HPV, which contains
an oncogene that produces E7 protein
• E7 binds RB and prevents it from properly
controlling the cell cycle
© 2012 Pearson Education, Inc.
Figure 24-17, Right
© 2012 Pearson Education, Inc.
The p53 Tumor Suppressor Gene Is
the Most Frequently Mutated Gene in
Human Cancers
• One of the most important tumor suppressor genes
identified is the p53 gene (TP53 in humans)
• About 50% of all cancers have p53 mutations
• p53 responds to DNA damage by arresting the cell
cycle to allow DNA repair, and triggering apoptosis
if repairs cannot be made
© 2012 Pearson Education, Inc.
p53 in cancer
• Inactivation of p53 leads to a failure of apoptosis,
and allows defective cells to continue to divide
• An inherited condition, Li-Fraumeni syndrome, is
caused by a defective copy of the p53 gene and is
characterized by the development of various types
of cancers by early adulthood
• These are caused by mutations in the second copy
of p53
© 2012 Pearson Education, Inc.
p53 is a target for certain cancer viruses
• HPV has a second oncogene that produces the
E6 protein
• E6 directs attachment of ubiquitin to p53 and
targets it for destruction
• Therefore, HPV blocks the action of both the Rb
and p53 proteins
© 2012 Pearson Education, Inc.
Figure 24-18
© 2012 Pearson Education, Inc.
The APC Tumor Suppressor Gene
Codes for a Protein That Inhibits the
Wnt Signaling Pathway
• The APC gene is associated with an inherited
disease called familial adenomatous polyposis
• Individuals who inherit a mutation in the gene are
susceptible to developing polyps (benign tumors) in
the colon if the second copy of APC is mutated
• APC mutations can also arise spontaneously or be
triggered by mutagens
© 2012 Pearson Education, Inc.
APC and Wnt signaling
• The APC gene produces a protein involved in the
Wnt pathway, which plays a role in controlling
proliferation and differentiation during embryonic
development
• The central component is b-catenin, which is
regulated by a multiprotein destruction complex
(APC, axin, and GSK3)
• The destruction complex targets b-catenin for
destruction
© 2012 Pearson Education, Inc.
Activation of Wnt
• The Wnt pathway is turned on by Wnt signaling
proteins that bind and activate cell surface Wnt
receptors
• The activated receptors bind axin, and prevent
assembly of the destruction complex
• b-catenin enters the nucleus, binds the TCT
transcription factor, and activates genes
(e.g., MYC, CYCD1) that stimulate proliferation
© 2012 Pearson Education, Inc.
APC and cancer
• Defects in the APC gene prevent the formation of
the destruction complex, leading to constitutive
Wnt signaling
• Thus cells receive a continuous signal to divide
© 2012 Pearson Education, Inc.
Figure 24-19A
© 2012 Pearson Education, Inc.
Figure 24-19B
© 2012 Pearson Education, Inc.
Figure 24-19C
© 2012 Pearson Education, Inc.
Inactivation of Some Tumor
Suppressor Genes Leads to Genetic
Instability
• Genetic instability refers to the fact that mutation
rates in cancer cells are thousands of times higher
than normal
• This state can arise in several ways
• One group of mechanisms involves disruptions in
DNA repair (e.g., HNPCC and Xeroderma
pigmentosum)
© 2012 Pearson Education, Inc.
Faulty DNA repair and breast cancer
• Most hereditary forms of breast cancer arise in
women who inherit a mutant copy of either
BRCA1 or BRCA2
• Both of these genes code for proteins involved in
repair of double-strand DNA breaks
• Breast and ovarian cells with these mutations
exhibit chromosomal rearrangements
© 2012 Pearson Education, Inc.
Faulty DNA repair and breast cancer
• Women inheriting BRCA mutations exhibit a 40–
80% lifetime risk for breast cancer and a 15–65%
risk for ovarian cancer
• Genetic testing is available for women with a family
history of breast cancer
© 2012 Pearson Education, Inc.
Genetic instability
• Most cancers are not hereditary but still exhibit
genetic instability
• In some cases the instability can be traced to
mutations in DNA repair genes
• The p53 pathway is defective in most cancer cells,
removing an important protective mechanism
against genetic instability
© 2012 Pearson Education, Inc.
Defects in mitosis
• Genetic instability can arise from defects that
cause disruptions in chromosome sorting during
cell division
• This results in broken chromosomes and
aneuploidy (abnormal number of chromosomes)
• Sometimes extra centrosomes are present
(structures that guide spindle formation)
© 2012 Pearson Education, Inc.
Figure 24-20
© 2012 Pearson Education, Inc.
Mitotic spindle checkpoint
• Cancer cells may exhibit defects in the mitotic
spindle checkpoint, which normally prevents
anaphase until all the chromosomes are correctly
attached to the spindle
• Loss of this checkpoint due to mutations in the
genes that regulate it (e.g., Mad, Bub) can lead to
chromosome mis-segregation
© 2012 Pearson Education, Inc.
Gatekeepers and Caretakers
• Tumor suppressor genes such as APC, RB, p53
are called gatekeepers; their loss directly opens
the gates to excessive proliferation and formation
of tumors
• Genes involved in DNA repair and chromosome
sorting are called caretakers because they
maintain genetic stability but are not directly
involved in controlling proliferation
© 2012 Pearson Education, Inc.
Table 24-2
© 2012 Pearson Education, Inc.
Cancers Develop by the Stepwise
Accumulation of Mutations Involving
Oncogenes and Tumor Suppressor
Genes
• Sequencing studies show that a given type of
cancer typically involves mutations in 50–75 genes
• A few of these are mutated frequently in samples
from different people; the commonly mutated genes
affect about a dozen different pathways
© 2012 Pearson Education, Inc.
Combinations of mutations
• The common mutations in cancers involve
inactivation of tumor suppressor genes and
conversion of proto-oncogenes to oncogenes
• The most common pattern detected in colon cancer
is active KRAS oncogene plus a mutation in tumor
suppressor genes APC, SMAD4, and p53
• Benign tumors have two of these; rapidly growing
cancers have all four
© 2012 Pearson Education, Inc.
Stepwise development of colon cancer
• The earliest mutation to be routinely detected is
loss of function of APC often in small polyps before
cancer has arisen
• Mutations in KRAS and SMAD4 are seen when
polyps grow larger
• Mutations in p53 accompany the development of
cancer (the steps do not always occur in this order
nor involve the exact set of genes)
© 2012 Pearson Education, Inc.
Figure 24-21
© 2012 Pearson Education, Inc.
The TGFb-Smad pathway
• The TGFb-Smad pathway is frequently disrupted
in colon cancer; this pathway inhibits epithelial cell
proliferation
• Loss of function mutations in this pathway disrupts
the inhibitory function, and is commonly detected
in colon cancers
© 2012 Pearson Education, Inc.
Epigenetic Changes in Gene
Expression Influence the Properties of
Cancer Cells
• Epigenetic changes alter a gene’s expression but
not its sequence
• E.g., DNA methylation at –CG- sites near promoters
can silence the adjacent genes
• Epigenetic silencing of numerous genes (tumor
suppressor genes) occurs in cancer cells, where
methylation levels are very high
© 2012 Pearson Education, Inc.
Epigenetic changes and cancer
predisposition
• People can inherit methylated genes
• Inheritance of methylated tumor suppressor genes
is associated with a predisposition to cancer
• E.g., inheritance of methylated MLH1, a DNA repair
gene, is associated to susceptibility with many
types of cancer
© 2012 Pearson Education, Inc.
MicroRNAs and cancer predisposition
• MicroRNAs bind to and silence translation of
thousands of mRNAs; cancer cells produce
excessive amounts of some miRNAs and
insufficient amounts of others
• Overproduced miRNAs that act as oncogenes
include miR-155, miR-17-92, and miR-21
• Underproduced miRNAs that act as tumor
suppressors include let-7, miR-29, and
miR-15a/miR-16-1
© 2012 Pearson Education, Inc.
Overproduced miRNAs
• miR-17-92 inhibits translation of PTEN, a
phosphatase that inhibits P13K-Akt signaling
pathways
• Overproduction of miR-17-92 in cancer cells leads
to constitutive activation of the P13K-Akt signaling
pathway and consequent enhancement of cell
proliferation
© 2012 Pearson Education, Inc.
Underproduced miRNAs
• The miR-15a/miR-16-1 cluster is often deleted in
certain forms of leukemia
• One of the functions of these miRNAs is to inhibit
synthesis of Bcl-2, a protein that inhibits apoptosis
• Too little miR-15a/miR-16-1 leads to less inhibition
of Bcl-2 and thus less ability of a cell to carry out
apoptosis if the need arises
© 2012 Pearson Education, Inc.
miRNAs and histones
• Some miRNAs influence histone modifications
• miR-101 is frequently deleted in prostate cancer;
this miRNA normally inhibits synthesis of EZH2, a
protein that catalyzes histone methylation
• Loss of miR-101 is therefore associated with
increased histone methylation and the silencing of
tumor suppressor genes
© 2012 Pearson Education, Inc.
Summing Up: Carcinogenesis and the
Hallmarks of Cancer
• Carcinogenesis is the multistep process that
converts normal cells into cancer cells
• The four main causes of cancer are chemicals,
radiation, infectious agents, heredity
• Six traits have been described as the hallmarks of
cancer; these traits uncouple cancer cells from the
normal limits on proliferation and growth
© 2012 Pearson Education, Inc.
The hallmarks of cancer
1. Self-sufficiency in growth signals
– Normal cells require growth cells to proliferate, but
cancer cells escape this requirement
2. Insensitivity to antigrowth signals
– Normal tissues are protected from overproliferation
by a variety of inhibitory signals, but cancer cells are
insensitive to these signals
© 2012 Pearson Education, Inc.
The hallmarks of cancer (continued)
3. Self-sufficiency in growth signals
– Apoptosis is used by normal cells to prevent
damaged or defective cells from continuing to divide;
apoptosis is inhibited or disrupted in cancer cells
4. Limitless replicative potential
– Normal cells have limited replicative potential due to
telomere loss; cancer cells contain active telomerase
(or other mechanisms) to maintain telomeres
© 2012 Pearson Education, Inc.
The hallmarks of cancer (continued)
5. Sustained angiogenesis
– Tumor cells cannot grow beyond a few mm without a
blood supply; cancer cells trigger angiogenesis by
activating genes coding for angiogenesis stimulators
and inhibiting genes coding for angiogenesis
inhibitors
6. Tissue invasion and metastasis
– Cancer cells lose adhesiveness with neighbors,
invade nearby tissues, and eventually metastasize
around the body via the circulatory system
© 2012 Pearson Education, Inc.
The Crucial Enabling Trait: Genetic
Instability
• To acquire the six traits that lead to cancer, cells
must accumulate more mutations that could be
generated by normal mutation rates
• Genetic instability arises most frequently from
disruption of the p53 pathway, but also occurs due
to mutations affecting DNA repair and
chromosome sorting
© 2012 Pearson Education, Inc.
Figure 24-22
© 2012 Pearson Education, Inc.
Diagnosis, Screening, and Treatment
• Much progress has been made in recent years in
elucidating the processes underlying cancer
development
• The aim of such research is to use understanding
of the underlying molecular alterations that occur
in cancer to improve strategies for diagnosis and
treatment
© 2012 Pearson Education, Inc.
Cancer Is Diagnosed by Microscopic
Examination of Tissue Specimens
• Definitive diagnosis typically requires a biopsy,
surgical removal of a tissue sample for microscopic
examination
• Cancer cells usually have large, irregularly shaped
nuclei, prominent nucleoli, and abnormal tissue
organization
• They have more dividing cells than normal (an
elevated mitotic index) and poorly defined outer
boundaries
© 2012 Pearson Education, Inc.
Table 24-3
© 2012 Pearson Education, Inc.
Tumor grading
•
Tumor grading is the assignment of numbered
grades to tumors depending on the severity of the
abnormal traits they display
•
Lower numbers are assigned to tumors with fewer or
less severe abnormalities
•
The highest-grade cancers contain cells so abnormal
that they no longer resemble the cells of origin; these
are the most aggressive and difficult to treat
© 2012 Pearson Education, Inc.
Screening Techniques for Early
Detection Can Prevent Cancer Deaths
• Cancers that are detected before they spread have
relatively high cure rates
• One of the most successful screening procedures is
the Pap smear, used for detecting cervical cancer
• A small sample of vaginal secretions is examined
microscopically to determine if the cells in the fluid
exhibit abnormalities—these are a sign that cancer
might be present and further tests are needed
© 2012 Pearson Education, Inc.
Figure 24-23
© 2012 Pearson Education, Inc.
Other types of routine screening
• Mammography, an X-ray technique to detect early
signs of breast cancer
• Colonoscopy, using a fiber-optic instrument to
examine the colon for signs of colon cancer
• PSA test (prostate-specific antigen) tests the
amount of PSA in the blood; high levels indicate
possible prostate cancer
© 2012 Pearson Education, Inc.
Surgery, Radiation, and Chemotherapy
Are Standard Treatments for Cancer
• Strategies for treatment of cancer depend on the
type and how far it has spread
• Most commonly the primary tumor is removed
surgically, followed by radiation and/or
chemotherapy to destroy remaining cancer cells
• Radiation therapy uses high-energy X-rays to kill
cancer cells
© 2012 Pearson Education, Inc.
Radiation
• Radiation kills cells in two ways
• DNA damage caused by radiation activates the
p53 pathway, so if it is still functional in the tumor
cells, it can trigger apoptosis
• Radiation causes such severe DNA/chromosomal
damage that cells cannot proceed successfully
through mitosis
© 2012 Pearson Education, Inc.
Chemotherapy
• Most forms of chemotherapy use drugs that kill
dividing cells; these drugs fall into four categories
• 1. Antimetabolites inhibit metabolic pathways
required for DNA synthesis by competitively
inhibiting synthetic enzymes (e.g., fluorouracil,
methotrexate, fludarabine, pemetrexed,
gemcitabine)
© 2012 Pearson Education, Inc.
Chemotherapy drug categories
(continued)
• 2. Alkylating agents inhibit DNA function by
crosslinking the DNA double helix
(e.g., cyclophosphamide, chlorambucil, cisplatin)
• 3. Antibiotics are substances made by
microorganisms that inhibit DNA function by
binding DNA or inhibiting topoisomerases required
for replication (e.g., doxorubicin, epirubicin)
© 2012 Pearson Education, Inc.
Chemotherapy drug categories
(continued)
• 4. Plant-derived drugs that either inhibit
topoisomerases or disrupt microtubules of the
mitotic spindle (e.g., etoposide, taxol)
• A problem with these drugs and with radiation is
that they are toxic to normal dividing cells as well
as to cancer cells
• Less toxic approaches are possible for some types
of cancers
© 2012 Pearson Education, Inc.
Hormone-dependent tumors
• Some cancers require specific hormones for
growth, e.g., many breast cancers require estrogen
for their growth
• So preventing access of the cancer cells to the
needed hormone can be effective
• The drug tamoxifen binds the estrogen receptor,
and by preventing receptor activation can treat
breast cancer and prevent its occurrence in women
at risk
© 2012 Pearson Education, Inc.
Drug resistance
• Cancer cells tend to acquire mutations that make
them resistant to the chemotherapy drugs
• Multiple drug resistance arises when cancer cells
begin to produce multidrug resistance transport
proteins (ABC transporters) that pump a range of
chemically dissimilar drugs out of the cell
• Treatment that leaves behind a small number of
cancer stem cells may allow the tumor to
regenerate following treatment
© 2012 Pearson Education, Inc.
Using the Immune System to Target
Cancer Cells
• Immunotherapy can be used to treat some
aggressive types of cancer
• Triggering an immune response with the bacteria
bacillus Calmette Guérin elicits a strong immune
response in the patient
• Use of the bacteria in bladder cancers after
surgical removal of the tumor seems to reduce the
likelihood of recurrence
© 2012 Pearson Education, Inc.
Immunotherapy
• Treatment with proteins that the body uses to
stimulate the immune system are sometimes used,
e.g., Interferon alpha and interleukin-2
• Also attempts are underway to develop vaccines to
stimulate the immune system to attach cancer cells
• The vaccine Provenge uses an antigen commonly
found in prostate cancer cells
© 2012 Pearson Education, Inc.
Herceptin and Gleevec Attack Cancer
Cells by Molecular Targeting
• In molecular targeting drugs are designed to
specifically target those proteins critical to the
cancer cell
• The first antibody approved for use in cancer
patients is Herceptin, which binds and inactivates
the ERBB2 growth factor receptor (HER2)
• The antibody inhibits the receptor’s ability to
stimulate cell proliferation
© 2012 Pearson Education, Inc.
Other antibodies used in cancer therapy
• Erbitux is directed against the epidermal growth
factor receptor
• Avastin is directed against the angiogenesis
stimulating factor, VEGF
© 2012 Pearson Education, Inc.
Rational drug design
• Small molecule inhibitors can be designed that
target and inactivate particular proteins associated
with certain cancers
• This is called rational drug design
• One of the first drugs designed this way was
Gleevec, which binds and disables the abnormal
product of the BCR-ABL oncogene
© 2012 Pearson Education, Inc.
Anti-angiogenic Therapies Act by
Attacking a Tumor’s Blood Supply
• Tumor growth depends on angiogenesis, so it is
expected that inhibiting angiogenesis would be an
effective cancer treatment
• Anti-angiogenic therapy was found to make tumors
shrink in mice (Folkman)
• Avastin, the first anti-angiogenic drugs, binds and
inactivates VEGF
© 2012 Pearson Education, Inc.
Anti-angiogenesis treatment not yet
completely effective
• Though Avastin improves short-term survival rates
in some types of cancer, the benefits are usually
temporary
• Other drugs that target angiogenesis are currently
being evaluated
© 2012 Pearson Education, Inc.
Cancer Treatments Can Be Tailored to
Individual Patients
• In personalized medicine, treatment approaches
are tailored to the characteristics of each patient
• Transcriptome analysis can determine which genes
are being expressed in the cancer cells of each
tumor
• E.g., the expression of 21 key genes in breast
tumors is a good indication of likelihood of
metastasis
© 2012 Pearson Education, Inc.
Oncotype DX
• A test called Oncotype DX measures the activity of
the 21 key genes and generates a recurrence
score
• Women with a high recurrence score are most
likely to have their cancer recur after surgery
• Those with low recurrence scores may not need
unpleasant chemotherapy following surgery
© 2012 Pearson Education, Inc.
Iressa
• Iressa is a drug that acts by inhibiting the receptor
tyrosine kinase activity of the EGF receptor; it
works extremely well in about 10% of lung cancer
patients
• Its effectiveness is limited to patients whose
tumors contain mutant EGF receptor genes
• Patients whose lung tumors have this mutation will
benefit from Iressa treatment
© 2012 Pearson Education, Inc.