Transcript Cancer

19
Cancer
19 Cancer
• The Development and Causes of
Cancer
• Tumor Viruses
• Oncogenes
• Tumor Suppressor Genes
• Molecular Approaches to Cancer
Treatment
Introduction
Cancer results from a breakdown of
the regulatory mechanisms that
govern normal cell behavior.
Cancer cells grow and divide in an
uncontrolled manner, spreading
throughout the body and interfering
with the function of normal tissues
and organs.
Introduction
Cancer ultimately has to be understood
at the molecular and cellular levels.
Studies of cancer cells have also
illuminated the mechanisms that
regulate normal cell behavior.
The Development and Causes of Cancer
The loss of growth control exhibited by
cancer cells is the net result of
accumulated abnormalities in multiple
cell regulatory systems.
It is reflected in several aspects of cell
behavior that distinguish cancer cells
from their normal counterparts.
The Development and Causes of Cancer
There are more than 100 types of
cancer.
A tumor is any abnormal proliferation of
cells.
Benign tumors remain confined to the
original location, neither invading
surrounding normal tissue nor
spreading to distant body sites.
The Development and Causes of Cancer
A malignant tumor can invade
surrounding normal tissue and spread
throughout the body via the circulatory
or lymphatic systems (metastasis).
Only malignant tumors are properly
referred to as cancers.
Figure 19.1 A cancer of the pancreas
The Development and Causes of Cancer
Most cancers are in three main groups:
Carcinomas—malignancies of epithelial
cells (about 90% of human cancers).
Sarcomas—solid tumors of connective
tissue such as muscle, bone, cartilage,
and fibrous tissue (rare in humans).
The Development and Causes of Cancer
Leukemias and lymphomas arise from
the blood-forming cells and immune
system cells, respectively.
Tumors are further classified according
to tissue of origin and type of cell
involved.
The Development and Causes of Cancer
Only a few types of cancer occur
frequently.
The four most common cancers are
prostate, breast, lung, and
colon/rectum.
Lung cancer, by far the most lethal, is
responsible for nearly 30% of all cancer
deaths.
Table 19.1 Most Frequent Cancers in the United States
The Development and Causes of Cancer
A fundamental feature of cancer is tumor
clonality—tumors develop from single
cells that begin to proliferate
abnormally.
The single-cell origin has been
demonstrated by analysis of X
chromosome inactivation patterns.
Figure 19.2 Tumor clonality
The Development and Causes of Cancer
The development of cancer is a
multistep process: cells gradually
become malignant through a
progressive series of alterations.
One indication of this is that most
cancers develop late in life.
Most cancers develop as a consequence
of multiple abnormalities, which
accumulate over many years.
Figure 19.3 Increased rate of cancer with age
The Development and Causes of Cancer
At the cellular level, development of
cancer is a multistep process:
Mutation and selection for cells with
progressively increasing capacity for
proliferation, survival, invasion, and
metastasis.
The Development and Causes of Cancer
Tumor initiation: mutation leads to
abnormal proliferation of a single cell,
which grows into a population of clonal
tumor cells.
Tumor progression: additional mutations
occur within cells of the tumor
population.
Figure 19.4 Stages of tumor development
The Development and Causes of Cancer
Tumor cells have high frequency of
mutations and chromosome
abnormalities.
Some mutations may confer selective
advantage, such as rapid growth.
The Development and Causes of Cancer
Clonal selection: Descendents of these
cells become dominant.
Clonal selection continues throughout
tumor development, so tumors
continuously become more rapidgrowing and increasingly malignant.
The Development and Causes of Cancer
Colon carcinoma is an example of tumor
progression.
Proliferation of colon epithelial cells
gives rise to a small benign neoplasm
(an adenoma or polyp).
Clonal selection leads to growth of
adenomas of increasing size and
proliferative potential.
The Development and Causes of Cancer
Malignant carcinomas arise from the
benign adenomas; tumor cells invade
the underlying connective tissue.
Eventually the cancer cells penetrate the
colon walls and invade other abdominal
organs, blood, and lymphatic vessels.
Figure 19.5 Development of colon carcinomas (Part 1)
Figure 19.5 Development of colon carcinomas (Part 2)
The Development and Causes of Cancer
Carcinogens are substances that cause
cancer.
Radiation and many chemical carcinogens
damage DNA and induce mutations:
• Solar ultraviolet radiation—the major
cause of skin cancer.
• Aflatoxin—produced by some molds
that contaminate peanuts and stored
grains.
The Development and Causes of Cancer
• Chemicals in tobacco smoke include
benzo(α)pyrene,
dimethylnitrosamine, and nickel
compounds.
It is estimated that smoking is
responsible for nearly one-third of all
cancer deaths.
Figure 19.6 Structure of representative chemical carcinogens
The Development and Causes of Cancer
Other carcinogens are tumor promoters
that stimulate cell proliferation.
• Hormones, particularly estrogens, are
tumor promoters in some human
cancers.
Exposure to excess estrogen
significantly increases the likelihood that
a woman will develop uterine cancer.
The Development and Causes of Cancer
• Asbestos
• The bacterium Heliobacter pylori
causes stomach cancer.
• Some viruses cause cancer, including
liver cancer and cervical carcinoma.
Studies of tumor viruses have helped
elucidate molecular events in the
development of all types of cancers.
The Development and Causes of Cancer
Cancer cells have characteristic properties
that distinguish them from normal cells
and contribute to malignancy:
1. Uncontrolled proliferation
2. Reduced dependence on growth
factors
3. Reduced cell adhesion molecules
4. Secretion of proteases
The Development and Causes of Cancer
5. Promotion of angiogenesis
6. Abnormal differentiation
7. Failure to undergo apoptosis
8. Capacity for unlimited replication
The Development and Causes of Cancer
1. In culture, normal cells display
density-dependent inhibition:
They proliferate until reaching a finite
cell density, determined partly by
availability of growth factors.
They then cease proliferating and are
arrested in the G0 stage of the cell
cycle.
The Development and Causes of Cancer
Cancer cells are not restricted by growth
factor availability or cell–cell contact.
They don’t respond to the signals that
cause normal cells to cease
proliferation, but grow to high densities
in culture.
Figure 19.7 Density-dependent inhibition
The Development and Causes of Cancer
Normal fibroblasts show contact inhibition:
They migrate across a culture dish until
making contact with a neighboring cell.
Normal cells adhere to each other,
forming an orderly array.
Tumor cells continue moving after contact,
migrating over adjacent cells, growing in
disordered, multilayered patterns.
Figure 19.8 Contact inhibition
The Development and Causes of Cancer
2. Many cancer cells can grow in the
absence of growth factors required by
normal cells.
Some cancer cells produce growth
factors that stimulate their own
proliferation (autocrine growth
stimulation).
Figure 19.9 Autocrine growth stimulation
The Development and Causes of Cancer
Reduced growth factor dependence can
also result from abnormalities in
intracellular signaling systems.
Example: unregulated activity of growth
factor receptors or other proteins (e.g.,
Ras proteins or protein kinases).
The Development and Causes of Cancer
3. Cancer cells are less regulated by cell–
cell and cell–matrix interactions.
Most cancer cells are less adhesive than
normal cells, due to reduced expression
of cell surface adhesion molecules.
Loss of E-cadherin is important in
development of carcinomas (epithelial
cancers).
The Development and Causes of Cancer
Reduced adhesion molecules make
cancer cells less restrained by
interactions with other cells and the
matrix, contributing to their ability to
invade and metastasize.
Many tumor cells are rounder than
normal; they are less firmly attached to
either the matrix or neighboring cells.
The Development and Causes of Cancer
4. Cancer cells secrete proteases that
digest extracellular matrix components,
allowing them to invade adjacent
normal tissues.
Example: Proteases that digest
collagen allow carcinomas to penetrate
the basal laminae and invade
underlying connective tissue.
The Development and Causes of Cancer
5. Cancer cells secrete growth factors that
promote formation of new blood vessels
(angiogenesis).
When a tumor reaches about a million
cells, new blood vessels are needed to
supply oxygen and nutrients.
The new capillaries are easily penetrated
by tumor cells, contributing to metastasis.
The Development and Causes of Cancer
6. Most cancer cells don’t differentiate
normally.
This is coupled to abnormal proliferation;
normal cells cease cell division once
fully differentiated. Cancer cells are
blocked at an early stage of
differentiation.
The Development and Causes of Cancer
Example: Leukemias
All types of blood cells are derived from
stem cells in the bone marrow. Once
they are fully differentiated, cell division
ceases.
Leukemic cells don’t undergo terminal
differentiation; they are arrested at
early stages and retain the capacity for
proliferation.
Figure 19.10 Defective differentiation and leukemia
The Development and Causes of Cancer
Growth of leukemias, and some solid
tumors, may be driven by proliferation
of a subpopulation of cancer stem cells,
rather than proliferation of all cells in
the tumor.
Chronic myeloid leukemia arises from
oncogenic transformation of the
hematopoietic stem cells.
The Development and Causes of Cancer
7. Many cancer cells fail to undergo
programmed cell death or apoptosis
and have longer life spans than normal
cells.
Tumor cells are often able to survive in
the absence of growth factors required
by normal cells.
The Development and Causes of Cancer
Normal cells also undergo apoptosis
following DNA damage, while many
cancer cells do not.
This contributes to resistance of cancer
cells to irradiation and many
chemotherapeutic drugs, which act by
damaging DNA.
The Development and Causes of Cancer
8. Normal cells have limited amounts of
telomerase and gradually lose
telomeres, leading to cessation of
replication.
Cancer cells express high levels of
telomerase, allowing them to maintain
chromosome ends for an indefinite
number of divisions.
The Development and Causes of Cancer
Study of tumor induction was advanced
by development of in vitro assays to
detect cell transformation—
conversion of normal cells to tumor
cells.
Assays are designed to detect
transformed cells, which display the in
vitro growth properties of tumor cells.
The Development and Causes of Cancer
Focus assay:
Based on the ability to recognize a group
of transformed cells as a
morphologically distinct “focus” against
a background of normal cells on the
surface of a culture dish.
Figure 19.11 The focus assay
The Development and Causes of Cancer
The focus assay takes advantage of
three properties of transformed cells:
Altered morphology, loss of contact
inhibition, and loss of densitydependent inhibition of growth.
The Development and Causes of Cancer
Cells transformed in vitro can form
tumors following inoculation into
susceptible animals.
This supports in vitro transformation as a
valid indicator of the formation of
cancer cells.
Tumor Viruses
Tumor viruses can directly cause
cancer in humans or animals.
They have played a critical role in cancer
research by serving as models for cell
transformation.
They have small genomes, allowing
identification of viral genes responsible
for cancer induction.
Table 19.2 Tumor Viruses
Tumor Viruses
Hepatitis B and C viruses are the main
causes of liver cancer.
The viruses infect liver cells and can
lead to long-term chronic infections,
associated with a high risk of cancer.
The molecular mechanisms by which
they cause cancer are not well
understood.
Tumor Viruses
A viral protein may interact with p53
protein.
The chronic tissue damage and
inflammation in hepatitis B results in
continual proliferation of liver cells, and
may contribute to tumor development.
Tumor Viruses
Small DNA tumor viruses:
• Papillomaviruses: About 100
different types infect epithelial cells.
Some cause benign tumors (e.g.,
warts); others cause malignant
carcinomas, particularly cervical and
other anogenital cancers.
Tumor Viruses
Early detection and treatment of cervical
cancer is made possible by the Pap
smear test.
The cancer cells are easily detected by
microscopic examination.
Vaccines have also been developed for
cervical cancer viruses.
Tumor Viruses
• Polyomavirus
Merkel cell polyomavirus was
identified in 2008 as the cause of a rare
skin cancer, Merkel cell carcinoma.
SV40 and the adenoviruses don’t
cause human cancers, but have been
important as models for understanding
cell transformation.
Tumor Viruses
Replication of these viruses leads to
host cell lysis and release of progeny
virus particles.
But if viral replication is blocked,
expression of specific viral genes
results in transformation of the infected
cell.
Figure 19.12 Polyomavirus replication and transformation
Tumor Viruses
Genes that lead to cell transformation are
the same genes that function in early
stages of lytic infection.
Early region genes (expressed right after
infection) stimulate host gene
expression and DNA synthesis. This can
lead to transformation if the viral DNA
becomes stably integrated.
Tumor Viruses
Cell transformation by human
papillomaviruses results from
expression of early-region genes E6
and E7.
The proteins bind and inactivate host cell
tumor suppressor proteins Rb and p53.
The transforming proteins of SV40 and
adenoviruses similarly target Rb and
p53.
Figure 19.13 The genome of a human papillomavirus
Tumor Viruses
Herpesviruses are among the most
complex animal viruses, with genomes
of 100 to 200 kb.
Kaposi’s sarcoma-associated
herpesvirus and Epstein-Barr virus
cause human cancers.
Tumor Viruses
Epstein-Barr virus can also transform
human B lymphocytes in culture, but
the mechanisms are not fully
understood.
The transforming protein (LMP1) mimics
a surface receptor on B lymphocytes
and activates signaling pathways that
stimulate proliferation and inhibit
apoptosis.
Tumor Viruses
Kaposi’s sarcoma cells secrete
cytokines and growth factors that drive
tumor development.
Interestingly, the transforming proteins of
the virus appear to act at least in part
by stimulating growth factor secretion.
Tumor Viruses
Retroviruses cause cancer in many
animals, including humans.
Human T-cell lymphotropic virus type I
(HTLV-I) causes adult T-cell leukemia.
Tumor Viruses
AIDS is caused by the retrovirus HIV.
HIV does not cause cancer directly but
AIDS patients have a high incidence of
malignancies, particularly lymphomas
and Kaposi’s sarcoma.
They are associated with infection by
other viruses and develop as a
consequence of immunosuppression.
Tumor Viruses
Most retroviruses contain only three
genes (gag, pol, and env) that are
required for virus replication but play no
role in cell transformation.
Retroviruses of this type induce tumors
only rarely, if at all.
Figure 19.14 A typical retrovirus genome
Tumor Viruses
Other retroviruses contain genes that
induce cell transformation and are
potent carcinogens.
Rous sarcoma virus (RSV) is the
prototype of these highly oncogenic
retroviruses.
Studies of RSV led to identification of the
first viral oncogene.
Oncogenes
Oncogenes are specific genes that can
induce cell transformation.
Studies of viral oncogenes led to
identification of cellular oncogenes
involved in development of non-virusinduced cancers.
Oncogenes
RSV transforms chicken embryo
fibroblasts in culture and induces
sarcomas.
The closely related avian leukosis virus
(ALV) replicates in the same cells without
inducing transformation.
This suggested that RSV contains specific
genetic information for transformation.
Figure 19.15 Cell transformation by RSV and ALV
Oncogenes
In the 1970s, studies of RSV mutants
revealed a single gene responsible for
RSV tumor induction.
Because RSV causes sarcomas, the
oncogene was called src. It is not
present in ALV.
It encodes the first tyrosine kinase to be
identified.
Figure 19.16 The RSV and ALV genomes
Oncogenes
More than 40 oncogenic retroviruses
have been isolated.
All have at least one oncogene that is
not required for replication but is
responsible for cell transformation.
Many oncogenes encode components of
signaling pathways that stimulate cell
proliferation.
Table 19.3 Representative Retroviral Oncogenes
Oncogenes
Most viruses are streamlined to replicate
as efficiently as possible, so the
existence of viral oncogenes not
involved in replication was surprising.
Research into the origin of these genes
led to identification of cellular
oncogenes in human cancers.
Oncogenes
A clue to the origin of oncogenes came
from isolation of Abelson leukemia
virus from mice that had been injected
with nontransforming virus.
One mouse developed a lymphoma from
which a highly oncogenic virus was
isolated. It contained the oncogene abl.
Figure 19.17 Isolation of Abelson leukemia virus
Oncogenes
This suggested the hypothesis that
retroviral oncogenes are derived from
genes of the host cell.
Thus, normal cells must contain genes
that are closely related to the retroviral
oncogenes.
Oncogenes
This was demonstrated in 1976 by
Varmus and Bishop, who showed that a
cDNA probe for src hybridized to closelyrelated sequences in DNA of normal
chicken cells.
src-related sequences were also found in
normal DNAs in many vertebrates and
appeared to be highly conserved in
evolution.
Key Experiment, Ch. 19, p. 740 (3)
Oncogenes
Proto-oncogenes: normal-cell genes
from which retroviral oncogenes
originate.
They often encode proteins in the
signaling pathways that control normal
cell proliferation (e.g., src, ras, raf ).
Oncogenes are abnormally expressed or
mutated forms of the proto-oncogenes.
Oncogenes
Retroviral oncogenes differ from protooncogenes:
• Transcription in viral oncogenes is
controlled by viral promoters and
enhancers. Viral oncogenes are
usually expressed at much higher
levels than proto-oncogenes, or in
inappropriate cells.
Oncogenes
• Oncogenes often encode proteins that
differ in structure and function from
normal proteins.
• Oncogenes such as raf are expressed
as fusion proteins with viral
sequences at the amino terminus.
• Loss of regulatory domains generate
proteins that function in an
unregulated manner.
Figure 19.18 The Raf oncogene protein
Oncogenes
• Many oncogenes differ from the
proto-oncogenes by point mutations,
resulting in single amino acid
substitutions, which can also lead to
unregulated activity.
Oncogenes
Evidence for involvement of cellular
oncogenes in human tumors was found
in gene transfer experiments in 1981.
DNA from a human bladder carcinoma
was found to induce transformation of
mouse cells in culture, indicating that
the tumor contained an oncogene.
Figure 19.19 Detection of a human tumor oncogene by gene transfer
Oncogenes
Gene transfer assays and other
experimental approaches have
detected cellular oncogenes in many
types of human tumors.
Table 19.4 Representative Oncogenes of Human Tumors
Oncogenes
The first human oncogene identified was
the homolog of the rasH oncogene of
Harvey sarcoma virus.
Three members of the ras gene family
(rasH, rasK, and rasN) are the
oncogenes most frequently
encountered in human tumors.
Oncogenes
ras oncogenes are not present in normal
cells; they are generated in tumor cells
from mutations during tumor
development.
They differ from their proto-oncogenes
by point mutations resulting in single
amino acid substitutions. The mutations
are caused by chemical carcinogens.
Figure 19.20 Point mutations in ras oncogenes
Oncogenes
ras genes encode guanine-binding
proteins that function in transduction of
mitogenic signals from many growth
factor receptors.
Ras proteins alternate between active
(GTP-bound) and inactive (GDPbound) states.
Oncogenes
Mutations of ras oncogenes maintain the
Ras proteins constitutively in the active
GTP-bound conformation.
Oncogenic Ras proteins don’t respond to
GAP (GTPase-activating protein),
resulting in decreased GTPase activity.
Oncogenes
Many cancer cells have abnormal
chromosome structure, including
translocations, duplications, and
deletions.
These can lead to generation of
oncogenes.
Oncogenes
In Burkitt’s lymphoma, chromosome
translocation inserts c-myc oncogene
into an immunoglobulin locus, where it is
expressed in an unregulated manner.
c-myc encodes a transcription factor
normally induced in response to growth
factor stimulation.
Figure 19.21 Translocation of c-myc
Oncogenes
Translocations often result in
rearrangements of coding sequences
and abnormal gene products.
Example: Translocation of the abl protooncogene from chromosome 9 to
chromosome 22 in chronic myeloid
leukemia.
Figure 19.22 Translocation of abl (Part 1)
Oncogenes
The translocation leads to fusion of abl
with bcr, and production of a Bcr/Abl
fusion protein.
This results in unregulated activity of Abl
tyrosine kinase, leading to cell
transformation.
Figure 19.22 Translocation of abl (Part 2)
Oncogenes
Oncogenes can be activated by gene
amplification, resulting in elevated
expression.
Amplification is 1000 times more
common in tumor cells, and may play a
role in the progression of tumors to
more rapid growth and increasing
malignancy.
Oncogenes
Oncogene proteins can play many roles
in growth factor-stimulated signal
transduction pathways.
In the ERK pathway, oncogene proteins
include polypeptide growth factors,
growth factor receptors, intracellular
signaling proteins, and transcription
factors.
Figure 19.23 Oncogenes and the ERK signaling pathway
Oncogenes
Many oncogenes encode growth factor
receptors, mostly tyrosine kinases.
These receptors can be converted to
oncogene proteins by alterations of
amino-terminal domains, which would
normally bind extracellular growth
factors.
Oncogenes
The receptor for platelet-derived growth
factor (PDGFR) is converted to an
oncogene by a chromosome
translocation and replacement of the
amino terminus by a transcription factor
called Tel.
Oncogenes
Tel sequences of the Tel/PDGFR fusion
protein dimerize in the absence of
growth factor binding.
This results in constitutive activity of the
intracellular kinase domain and
unregulated production of a
proliferative signal from the oncogene
protein.
Figure 19.24 Mechanism of Tel/PDGFR oncogene activation
Oncogenes
Many oncogenes encode transcriptional
regulatory proteins that are normally
induced in response to growth factors.
Transcription of the fos proto-oncogene
is induced by phosphorylation of Elk-1
by ERK.
Oncogenes
Fos and Jun dimerize to form AP-1
transcription factor, which activates
transcription of cyclin D1.
Figure 19.25 The AP-1 transcription factor
Oncogenes
The gene encoding cyclin D1 can become
an oncogene (CCND1) by chromosome
translocation or gene amplification.
Constitutive expression of cyclin D1 drives
cell proliferation in the absence of normal
growth factor stimulation.
Cdk4 is also activated as an oncogene by
point mutations in melanomas.
Oncogenes
Components of other signaling pathways
can also act as oncogenes.
Wnt proteins were identified as
oncogenes in mouse breast cancers;
mutations convert the downstream
target of Wnt signaling, β-catenin, to an
oncogene (CTNNB1) in human colon
cancers.
Figure 19.26 Oncogenic activity of b-catenin (Part 1)
Figure 19.26 Oncogenic activity of b-catenin (Part 2)
Oncogenes
Oncogenic activity of some transcription
factors results from inhibition of cell
differentiation.
Mutated forms of thyroid hormone
receptor (ErbA) and retinoic acid
receptor (PML/RARα) are oncogene
proteins in chicken erythroleukemia and
human acute promyelocytic leukemia.
Oncogenes
The mutated oncogene receptors
interfere with the action of their normal
homologs, blocking cell differentiation
and maintaining the leukemic cells in
an actively proliferating state.
Figure 19.27 Action of the PML/RARa oncogene protein
Oncogenes
Acute promyelocytic leukemia can be
treated by retinoic acid, which induces
differentiation and blocks continued cell
proliferation.
Oncogenes
Several oncogenes encode proteins that
promote cell survival.
Oncogenes that encode growth factors,
growth factor receptors, and signaling
proteins such as Ras, stimulate cell
proliferation and also prevent cell
death.
Oncogenes
The PI 3-kinase/Akt signaling pathway
helps prevent apoptosis of many cells.
The genes encoding PI 3-kinase and
Akt act as oncogenes in both
retroviruses and human tumors.
Figure 19.28 Oncogenes and cell survival
Oncogenes
bcl-2 oncogene increases expression
of Bcl-2, which blocks apoptosis.
Identification of bcl-2 as an oncogene
demonstrated the significance of
apoptosis in cancer development.
It also led to discovery of the role of
bcl-2 and related genes as central
regulators of apoptosis.
Tumor Suppressor Genes
Tumor suppressor genes normally
inhibit cell proliferation and tumor
development.
In many tumors, these genes are lost or
inactivated, contributing to abnormal
proliferation of tumor cells.
Tumor Suppressor Genes
Tumor suppression was first noticed
during somatic cell hybridization
experiments in 1969.
Hybrids of normal and tumor cells were
not capable of forming tumors,
suggesting there were genes in the
normal cell that suppressed tumors.
Figure 19.29 Suppression of tumorigenicity by cell fusion
Tumor Suppressor Genes
The first tumor suppressor gene was
identified in studies of retinoblastoma,
an inherited childhood eye tumor.
About 50% of children of an affected
parent develop retinoblastoma,
indicating a single dominant gene that
confers susceptibility to tumor
development.
Figure 19.30 Inheritance of retinoblastoma
Tumor Suppressor Genes
One defective copy of the Rb tumor
suppressor gene is inherited, but
development of retinoblastoma requires
a second somatic mutation leading to
loss of the normal Rb allele.
Noninherited retinoblastoma is thus very
rare, since its development requires two
independent somatic mutations.
Figure 19.31 Mutations of Rb during retinoblastoma development (Part 1)
Figure 19.31 Mutations of Rb during retinoblastoma development (Part 2)
Figure 19.31 Mutations of Rb during retinoblastoma development (Part 3)
Figure 19.31 Mutations of Rb during retinoblastoma development (Part 4)
Tumor Suppressor Genes
The function of Rb as a negative
regulator of tumorigenesis was
indicated by chromosome morphology.
Visible deletions of chromosome 13q14
were found in some retinoblastomas,
suggesting that loss (rather than
activation) of the Rb gene led to tumor
development.
Figure 19.32 Rb deletions in retinoblastoma
Tumor Suppressor Genes
Rb is involved in other tumors; it is lost
or inactivated in many bladder, breast,
and lung carcinomas.
Also, oncogene proteins of several DNA
tumor viruses, including SV40,
adenoviruses, and human
papillomaviruses, bind to Rb and inhibit
its activity.
Figure 19.33 Interaction of Rb proteins with oncogene proteins of DNA tumor viruses
Tumor Suppressor Genes
Additional tumor suppressor genes have
now been identified.
Mutations of some tumor suppressor
genes appear to be the most common
molecular alterations leading to human
tumor development.
Table 19.5 Representative Tumor Suppressor Genes
Tumor Suppressor Genes
p53 was the second tumor repressor
gene identified.
It is inactivated in many cancers,
including leukemias, lymphomas,
sarcomas, brain tumors, and
carcinomas.
Mutations of p53 play a role in about
50% of all cancers.
Tumor Suppressor Genes
The proteins encoded by most tumor
suppressor genes inhibit cell
proliferation or survival.
In many cases, tumor suppressor proteins
inhibit the same cell regulatory pathways
that are stimulated by the products of
oncogenes.
Tumor Suppressor Genes
The PTEN tumor suppressor gene
encodes a lipid phosphatase that
dephosphorylates PIP3.
This inhibits PI 3-kinase and Akt, which
can both act as oncogenes by
promoting cell survival, and stimulating
cell proliferation.
Figure 19.34 Suppression of cell proliferation and survival by PTEN
Tumor Suppressor Genes
Several tumor suppressor genes encode
transcriptional regulatory proteins.
Smad2 and Smad4 encode transcription
factors that are activated by TGF-β
signaling and lead to inhibition of cell
proliferation.
The TGF-β receptor is also encoded by
a tumor suppressor gene (TβRII).
Tumor Suppressor Genes
Products of Rb and INK4 tumor
suppressor genes regulate the cell
cycle at the point also affected by cyclin
D1 and Cdk4, which can both act as
oncogenes.
Rb inhibits passage through the
restriction point in G1. INK4 encodes
the Cdk inhibitor p16.
Tumor Suppressor Genes
Mutational inactivation of Rb in tumors
thus removes a key negative regulator
of cell cycle progression.
p16 inhibits Cdk4, 6/cyclin D activity.
Inactivation of INK4 leads to elevated
activity of Cdk4, 6/cyclin D, resulting in
uncontrolled phosphorylation of Rb.
Figure 19.35 Inhibition of cell cycle progression by Rb and p16
Tumor Suppressor Genes
p53 gene product regulates both cell
cycle progression and apoptosis.
DNA damage leads to induction of p53,
which activates transcription of both
proapoptotic and cell cycle inhibitory
genes.
Figure 19.36 Action of p53
Tumor Suppressor Genes
Cells lacking p53 fail to undergo
apoptosis in response to DNA damage,
leading to increased mutation
frequencies.
Loss of p53 also interferes with
apoptosis induced by other stimuli,
such as growth factor deprivation and
oxygen deprivation.
Tumor Suppressor Genes
BRCA1 and BRCA2 genes (responsible
for some inherited breast and ovarian
cancers) are stability genes that
maintain the integrity of the genome.
Mutations and inactivation of stability
genes leads to high mutation frequency
in oncogenes or tumor suppressor
genes.
Tumor Suppressor Genes
MicroRNAs (miRNAs) are major
regulators of gene expression in
eukaryotes.
They act post-transcriptionally, to inhibit
translation and/or induce mRNA
degradation, contributing to regulation
of about half of protein-coding genes.
Tumor Suppressor Genes
Expression of miRNAs is low in tumors,
suggesting they may act as tumor
suppressors.
Example: let-7 targets oncogenes
including rasK and c-myc.
Figure 19.37 Action of let-7 miRNA as a tumor suppressor
Tumor Suppressor Genes
Other miRNAs can act as oncogenes.
Example: The miRNAs designated miR17-92 are amplified in some tumors
and target mRNAs encoding proteins
that inhibit cell cycle progression or
promote apoptosis.
Tumor Suppressor Genes
Development of cancer is a multistep
process in which normal cells gradually
progress to malignancy.
Accumulated damage to multiple genes
eventually results in increased
proliferation, survival, invasiveness,
and metastatic potential.
Tumor Suppressor Genes
Large-scale genome sequencing has
been used to analyze mutations in
oncogenes and tumor suppressor
genes in thousands of individual
cancers.
About 150 mutated genes have been
identified in tumors, but only subsets
are involved in cancers of any
particular type.
Tumor Suppressor Genes
Genes consistently mutated in colon
cancers include rasK and PI3K
oncogenes, and APC and p53 tumor
suppressor genes.
Breast cancers have frequent mutations
in p53 and PI3K.
Figure 19.38 Genetic alterations in colorectal and breast carcinomas (Part 1)
Figure 19.38 Genetic alterations in colorectal and breast carcinomas (Part 2)
Tumor Suppressor Genes
Different mutations can affect the same
signaling pathway.
Example: in colon cancer, mutations in
either rasK or B-raf stimulate ERK
signaling in the tumor cells. (Raf is
downstream of Ras).
Tumor Suppressor Genes
The large number of different mutations
in tumors affect a much smaller number
of complementary pathways that
regulate cell proliferation, survival, and
genome stability.
Figure 19.39 Pathways affected by human oncogenes and tumor suppressor genes
Molecular Approaches to Cancer Treatment
Much has been learned about the
molecular defects responsible for the
development of cancers.
Advances in molecular biology
contribute to development of new
approaches to cancer prevention and
treatment.
Molecular Approaches to Cancer Treatment
The most effective way to deal with
cancer is to prevent development of the
disease.
Second-best is reliable early detection of
premalignant stages that can be
treated easily.
Molecular Approaches to Cancer Treatment
Many cancers can be cured by localized
treatment, before they metastasize.
Early stages of colon cancer
(adenomas) are usually curable by
minor surgical procedures.
Figure 19.40 Survival rates of patients with colon carcinoma
Molecular Approaches to Cancer Treatment
Molecular biology can be used to identify
individuals with inherited susceptibilities
to cancer development.
Mutations in tumor suppressor genes,
oncogenes (ret and cdk4), stability
genes (BRCA1 and BRCA2), and
others, can be detected with genetic
testing.
Molecular Approaches to Cancer Treatment
Some patients at high risk may choose
prophylactic surgery to prevent cancer
from developing.
Monitoring of high-risk individuals can
allow early detection and treatment.
Molecular Approaches to Cancer Treatment
Most cancer drugs damage DNA or
inhibit DNA replication and are toxic to
normal cells as well, especially cells
that are continually replaced by division
of stem cells (hematopoietic cells,
epithelial cells of the gastrointestinal
tract, hair follicle cells)
Molecular Approaches to Cancer Treatment
One new approach uses drugs that
interfere with angiogenesis (blood
vessel formation) or disrupt tumor
blood vessels.
These drugs block proliferation of
endothelial cells, and are less toxic to
normal cells.
Molecular Approaches to Cancer Treatment
Some drugs are targeted specifically
against oncogenes.
This is tricky, since proto-oncogenes
play important roles in normal cells and
can be targeted also.
But several selective oncogene-targeted
therapies have been developed.
Table 19.6 Representative Oncogene-Targeted Therapies
Molecular Approaches to Cancer Treatment
The first of these therapies was used to
treat acute promyelocytic leukemia.
The gene for retinoic acid receptor
(RARα) is fused with PML to form the
PML/RARα oncogene; the resulting
protein blocks cell differentiation.
High doses of retinoic acid inactivates
the PML/RARα protein.
Molecular Approaches to Cancer Treatment
Monoclonal antibody treatments have
been developed against extracellular
targets, such as growth factors or cell
surface receptors.
Molecular Approaches to Cancer Treatment
Herceptin: a monoclonal antibody
against the ErbB-2 oncogene protein,
which is over-expressed in many breast
cancers as a result of amplification of
erbB-2 gene.
Erbitux; monoclonal antibody against
EGF receptor (the ErbB oncogene
protein); used to treat colorectal
cancer.
Molecular Approaches to Cancer Treatment
Small molecule inhibitors of oncogene
proteins, such as protein kinases, are
also being developed.
An inhibitor of the Bcr/Abl tyrosine
kinase (called imatinib or Gleevec)
effectively blocks proliferation of
chronic myeloid leukemia cells.
Molecular Medicine, Ch. 19, p. 763
Figure 19.41 Effect of imatinib on mortality from chronic myeloid leukemia
Molecular Approaches to Cancer Treatment
A few patients develop resistance to
imatinib, which most often results from
mutations of the Bcr/Abl protein kinase
domain that prevents imatinib binding.
Analysis of resistant mutants has
resulted in design of new inhibitors that
are currently being tested.
Molecular Approaches to Cancer Treatment
Imatinib also inhibits the PDGF receptor
and Kit tyrosine kinases.
Kit is an oncogene in about 90% of
gastrointestinal stromal tumors.
Imatinib is also active against other
types of tumors in which the PDGF
receptor is activated as an oncogene.
Molecular Approaches to Cancer Treatment
Two small molecule inhibitors of the
EGF receptor (gefitinib and erlotinib)
are effective for some lung cancers.
These cancers have mutations resulting
in constitutive activation of the EGF
receptor tyrosine kinase.
Inhibition of the EGF receptor was an
effective treatment.
Molecular Approaches to Cancer Treatment
Vemurafenib is approved for treatment of
melanoma. It has high affinity for the
mutated B-Raf oncogene proteins in
many melanomas.
In 2012, an inhibitor of Hedgehog
signaling was approved for basal cell
carcinomas with oncogenic mutations of
the Hedgehog receptor Smoothened.
Molecular Approaches to Cancer Treatment
Oncogene addiction: sensitivity of
tumors to inhibition of activated
oncogenes.
Proliferation and survival of tumor cells
become dependent on the oncogene.
In normal cells, alternative signaling
pathways can compensate if one
pathway is blocked.
Molecular Approaches to Cancer Treatment
Effectiveness of many oncogenetargeted therapies is limited by
development of resistance.
Resistance can result from mutations in
the targeted kinase, activation of other
tyrosine kinases, and activation of
downstream oncogenic pathways.
Molecular Approaches to Cancer Treatment
Preventing drug resistance, possibly by
combining multiple targeted therapies,
is a major focus of ongoing research.
Molecular Approaches to Cancer Treatment
The apparent dependence of cancer
cells on mutationally-activated
oncogenes offers the promise that
oncogene-targeted drugs combined
with genomic sequencing of tumors
may lead to major advances in
personal cancer treatment.