Cancer

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CANCER AS A MICROEVOLUTIONARY
PROCESS
• The body of an animal operates as a society or ecosystem
• Self-sacrifice—as opposed to survival of the fittest—is the rule
• the cells of a multicellular organism must be committed to
collaboration.
• Molecular disturbances upset this harmony
• A human body has more than 1013 cells
• Billions of cells experience mutations every day
• Disrupt the social controls.

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Cancer Cells Bypass Normal Proliferation
Controls and Colonize Other Tissues
Two heritable properties of cancer cells :
1. reproduce in defiance of the normal restraints on cell growth and division
2. invade and colonize territories normally reserved for other cells.
An abnormal cell that goes through successive and inappropriate rounds of
growth and division to proliferate out of control will give rise to a tumor, or
neoplasm—literally, a new growth.
A tumor is considered a true cancer only if it is malignant; that is, when its
cells have acquired the ability to invade surrounding tissue.
Invasiveness is an essential characteristic of cancer cells. It allows them to
break loose, enter blood or lymphatic vessels, and form secondary tumors
called metastases at other sites in the body. In general, the more widely a
cancer spreads, the harder it becomes to eradicate. It is metastases that
usually kill the cancer patient by causing failure of a vital organ.

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Benign versus malignant tumors

• A benign glandular tumor (pink cells; an

adenoma) remains inside the basal lamina
(yellow) that marks the boundary of the
normal structure (a duct, in this example).

• A malignant glandular tumor (red cells; an

adenocarcinoma) can develop from a benign
tumor cell, and it destroys the integrity of
the tissue.

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Classification of cancers
Cancers are traditionally classified according to the tissue and
cell type from which they arise.
1. Carcinoma is the name given to cancers arising from epithelial
cells.
2. Adenoma is a benign epithelial tumor with a glandular
organization; the corresponding type of malignant tumor is an
adenocarcinoma.

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Most cancers have characteristics that reflect
their origin
• the cells of a basal-cell carcinoma, derived from a keratinocyte
stem cell in the skin, generally continue to synthesize
cytokeratin intermediate filaments
• the cells of a melanoma, derived from a pigment cell in the skin,
will often (but not always) continue to make pigment granules.
• Cancers originating from different cell types are very different
diseases generally.
Basal-cell carcinomas of the skin are only locally invasive and rarely
metastasize
melanomas can become much more malignant and often form
metastases.

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Most Cancers Derive from a Single Abnormal
Cell
• The primary tumor is thought to arise by cell division from a
single cell that initially experienced some heritable change.
• Subsequently, additional changes have accumulated in some of
the descendants of this cell, allowing them to outgrow,
out-divide, and often outlive their neighbors.

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By the time it is first detected, a typical human cancer
will have been developing for many years and will
already contain a billion cancer cells or more

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 How can we be sure that the cancer cells are the
clonal descendants of a single abnormal cell?
Ans: through
molecular analysis of
the chromosomes in
tumor cells.

• Translocation between chromosomes 9 and 22

responsible for chronic myelogenous leukemia.
• When a reciprocal translocation occurs between them
at the indicated site, the result is the abnormal pair at
the bottom.
• The smaller of the two resulting abnormal
chromosomes (22q–) is called the Philadelphia
chromosome, after the city where the abnormality was
first recorded.

chronic myelogenous leukemia (CML)

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Cancer Cells Contain Somatic Mutations
• Tumor cells contain somatic mutations: they have one or more shared
detectable abnormalities in their DNA sequence that distinguish them from
the normal cells surrounding the tumor
• Cancers are also driven by epigenetic changes
persistent, heritable changes in gene expression that result from modifications of
chromatin structure without alteration of the cell’s DNA sequence.
• Somatic mutations that alter a DNA sequence appear to be a fundamental
and universal feature, and cancer is in this sense a genetic disease.
• Factors that cause genetic changes tend to provoke the development of
cancer. Thus, carcinogenesis can be linked to mutagenesis. This
correlation is particularly clear for two classes of external agents:
a) chemical carcinogens (which typically cause simple changes in the nucleotide
sequence), and
b) radiation, such as x-rays (which typically cause chromosome breaks and
translocations) or ultraviolet (UV) light (which causes specific DNA base
alterations).
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Factors that cause genetic changes tend to
provoke the development of cancer
a) chemical carcinogens
typically cause simple changes in the nucleotide sequence
b) radiation, such as x-rays (which typically cause chromosome breaks
and translocations) or ultraviolet (UV) light (which causes specific
DNA base alterations).

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A Single Mutation Is Not Enough to Change
a Normal Cell into a Cancer Cell
• Number of cells in a human body = 3.7 × 1013
• Number of cell division within the body over the course of a lifetime= 1016
• Cell proliferation occurs primarily in epithelia and the hemopoietic system and is balanced
by cell death to maintain normal tissue homeostasis.
• Spontaneous mutations
3/ per cell division = about 10–6 mutations per gene per cell division (in the absence of mutagen)
• This rate of error is unavoidable
limitations on the accuracy of DNA replication and repair.
every single human gene will have undergone mutation somewhere in the body on roughly 1010
separate occasions (over the course of a lifetime).
• Mutations in genes that
regulate cell growth and division, causing the cells to disobey the normal rules controlling cell
turnover.
Given the huge number of unavoidable mutations in a large organism like ourselves, the
problem of cancer might seem to be not why it occurs, but why it occurs so infrequently.

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 The huge number of unavoidable mutations:
Why cancer occurs why it occurs so infrequently

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Evidence indicate that the development of a cancer typically requires a
substantial number of independent, rare genetic and epigenetic accidents
occur in the lineage that emanates from a single cell.

Incidence of cancer as a function of age

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Many Cancers Develop Gradually Through
Successive Rounds of Random Inherited Change
Followed by Natural Selection
For those cancers known to have a specific external
cause, the disease does not usually become apparent
until long after exposure to the causal agent.

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Stages of development of cancer

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Clonal evolution during tumor progression
• a tumor develops through repeated rounds of mutation
and proliferation, giving rise to a clone of fully
malignant cancer cells.
• At each step, a single cell undergoes a mutation that
either enhances cell proliferation or decreases cell
death, so that its progeny become the dominant clone
in the tumor.
• Proliferation of each clone hastens the occurrence of
the next step of tumor progression by increasing the
size of the cell population that is at risk of undergoing
an additional mutation.
• Invasion through the basal lamina, an initial step in
metastasis.

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Cancers Can Evolve Abruptly Due to Genetic
Instability
• Unlike normal dividing cells, most human cancer cells
accumulate genetic changes at an abnormally rapid rate and
are said to be genetically unstable.
• This instability provides a selective advantage by speeding the
process of tumor progression—allowing the subsequent
accumulation of many additional mutations required to produce
a cancer.
• The extent of the instability and its molecular origins differ from
cancer to cancer and from individual to individual, both in
severity and in character.

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Chromosome complements of colon cancers
showing different kinds of genetic instability.

A) The karyotype of a typical cancer shows many gross abnormalities in chromosome number
and structure. Considerable variation can also exist from cell to cell.
(B) The karyotype of a tumor that has a stable chromosome complement with few chromosomal
anomalies; the genetic abnormalities in these tumors are mostly invisible, having been created by defects
in DNA repair.

karyotype—the set of chromosomes as they appear at mitosis

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Cancer stem cells can be responsible for a tumor’s
growth and yet remain only a small part of the
tumor- cell population
❖ During the development of cancer, mutations
have the potential to subvert the normal
cellular differentiation program in multiple
ways:
❑ by leading to an overproliferation of transit
amplifying cells or
❑ to an inhibition of their terminal
differentiation or death.
❖ Mutations that lead to the generation of cancer
stem cells (capable of self-renewal), together
with much larger numbers of dividing transit
amplifying cells that are derived from the
cancer stem cells but have a limited capacity
for self-renewal

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A Common Set of Hallmarks Typically
Characterizes Cancerous Growth
1. Altered homeostasis that results in cells growing and dividing
at a faster rate than they die
2. Bypass of normal limits to cell proliferation
3. Evasion of cell-death signals
4. Altered cellular metabolism
5. Manipulation of the tissue environment to support cell survival
and to evade a deleterious immune response
6. Escape of cells from their home tissues and proliferation in
foreign sites (metastasis)

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Cancer Cells Display an Altered Control of
Growth and Homeostasis
• Mutability and large cell population numbers create
opportunities for mutations to occur
• The driving force for development of a cancer= selective
advantage possessed by the mutant cells.
• a mutation or epigenetic change can confer such an advantage
by
❖ increasing the rate at which a clone of cells proliferates or
❖ by enabling it to continue proliferating when normal cells would stop or
die. One of the most important properties of many types of cancer cells
is that they fail to undergo apoptosis when a normal cell would do so

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Both increased cell division and decreased
apoptosis can contribute to tumorigenesis.

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Transformed phenotype of Cancer cells
1. Abnormal Shape
2. Abnormal motility
3. Abnormal responses to growth factors in the culture medium
transformed cells no longer require all of the positive signals from their
surroundings that normal cells require. In addition, transformed cells fail to
recognize some negative influences.
4. the way they react to contact with the culture dish and with one
another.
Whereas most normal cells will not divide unless they are attached to the
surface, transformed cells will often divide even if held in suspension.
normal cells become inhibited from moving and dividing when the culture
reaches confluence (where the cells are touching one another), while
transformed cells continue moving and dividing even after confluence, and so
pile up in layer upon layer in the culture dish

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 Loss of contact inhibition by cancer cells in cell culture

• Most normal cells stop proliferating

once they have carpeted the dish with a
single layer of cells: proliferation
seems to depend on contact with the
dish and to be inhibited by contacts
with other cells—a phenomenon known
as contact inhibition.
• Cancer cells usually disregard these
restraints and continue to grow, so that
they pile on top of one another

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Human Cancer Cells Escape a Built-in Limit to Cell Proliferation

• Many normal human cells have a built-in limit to the number of

times that they can divide when stimulated to proliferate in
culture:
they permanently stop dividing after a certain number of population
doublings (25–50 for human fibroblasts).
• This cell-division-counting mechanism is termed replicative cell
senescence, and it generally depends on the progressive
shortening of the telomeres at the ends of chromosomes, a
process that eventually changes their structure.

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Human cancer cells avoid replicative cell
senescence in one of two ways
1. they reactivate the telomerase gene as they proliferate, so
that their telomeres do not shorten or become uncapped;
2. they can evoke a mechanism based on a DNA repair process
that depends on homologous recombination for elongating
their chromosome ends.
Regardless of the strategy used, the result is that the cancer cells
continue to proliferate under conditions when normal cells would
stop due to telomere erosion.

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Chromosomes have repeated base segments called
telomeres that shorten with each replication cycle
(cell division)

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Cancer Cells Have an Abnormal Ability to
Bypass Death Signals
• Internal disorder in the cell
danger signals in the faulty cell> activate protective measures to reverse and
cure this disorder
activate apoptosis
• Cancer cells generally contain mutations that drive the cell into an
abnormal state:
metabolic processes may be unbalanced
essential cell components may be produced in ill-matched proportions.
• when the cell’s homeostatic mechanisms are inadequate to cope with
an imposed disturbance (cell stress):
a prospective cancer cell must accumulate changes that disable the normal
safety mechanisms that would otherwise cause a cell that is stressed to
commit suicide by apoptosis.

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Cancer Cells Have Altered Sugar Metabolism
(A) non-proliferating cells normally
✔ oxidizes nearly all of the glucose that they import from
the blood to produce ATP through oxidative
phosphorylation that takes place in their mitochondria.
✔ when deprived of oxygen, these cells generate most of
their ATP from glycolysis, converting the pyruvate
produced to lactate in order to regenerate the NAD+
that they need to keep glycolysis going.
(B) Tumor cells will generally
✔ produce abundant lactate even in the presence of
oxygen.
✔ This results from a greatly increased rate of glycolysis
that is fed by a very large increase in the rate of glucose
import.
✔ In this way, tumor cells resemble the rapidly
proliferating cells in embryos, which likewise require
for biosynthesis a large supply of the small- molecule
building blocks that can be produced from imported
glucose
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 The tumor microenvironment plays a role in
tumorigenesis
Tumors consist of many cell types,
including
• cancer cells,
• endothelial cells,
• pericytes (vascular smooth muscle cells),
• fibroblasts, and
• inflammatory white blood cells.

Communication among these and other cell

types plays an important part in tumor
development.

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Cancer Cells Must Survive and Proliferate in
a Foreign Environment
• In order to kill us, cancer cells generally need to spread and
multiply at new sites in the body through a process called
metastasis.
• This is the most deadly aspect of cancer, being responsible for
90% of cancer-associated deaths.
• By spreading through the body, a cancer becomes almost
impossible to eradicate by either surgery or local irradiation.
• Metastasis is itself a multistep process: the cancer cells first
have to invade local tissues and vessels, move through the
circulation, leave the vessels, and then establish new cellular
colonies at distant sites.
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Metastasis is a multistep process
1. the cancer cells first have to invade local tissues and vessels
2. move through the circulation
3. leave the vessels, and
4. then establish new cellular colonies at distant sites

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 Steps in the process of metastasis:
the spread of a tumor from its site of origin to another organ
1. Tumor cells may enter the bloodstream
directly by crossing the wall of a blood
vessel, or, more commonly by crossing the
wall of a lymphatic vessel that ultimately
discharges its contents (lymph) into the
bloodstream.
2. Tumor cells that have entered a lymphatic
vessel often become trapped in lymph nodes
along the way, giving rise to lymph-node
metastases.

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Summary
• Cancer cells: grow and proliferate in defiance of normal controls and gain the ability to invade surrounding tissues
and colonize distant organs.
• By giving rise to secondary tumors, or metastases, they become difficult to eradicate by surgery or local irradiation.
• Cancers are thought to originate from a single cell that has experienced an initial mutation, but the progeny of this
cell must undergo many further changes to become cancerous.
• Tumor progression usually takes many years and reflects the operation of a Darwinian-like process of evolution, in
which somatic cells undergo mutation and epigenetic changes accompanied by natural selection and occasional
bursts of genomic chaos that give rise to heterogeneity.
• Cancer cells acquire a variety of special properties as they evolve, multiply, and spread.
• Their mutant genomes enable them to grow and divide in defiance of the signals that normally keep cell proliferation
under tight control.
• As part of the evolutionary process of tumor progression, cancer cells acquire a collection of additional abnormalities,
including defects in the controls that permanently stop cell division or induce apoptosis in response to cell stress or
DNA damage and defects in the mechanisms that normally keep cells from straying from their proper place. All of
these changes increase the ability of cancer cells to survive, grow, and divide in their original tissue and then to
metastasize, founding new colonies in foreign environments. The evolution of a tumor also depends on other cells
present in the tumor microenviron- ment, collectively called stromal cells, that the cancer attracts and manipulates.
• most cancer cells are genetically and/or epigenetically unstable.

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CANCER-CRITI
CAL GENES:
HOW THEY
ARE FOUND
AND WHAT
THEY DO

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This Photo by Unknown Author is licensed under CC
Cancer depends on the accumulation of
heritable changes in somatic cells
• How can we understand it at a molecular level?
identify the mutations and epigenetic alterations involved
discover how they give rise to cancerous cell behavior.
1. finding the relevant cells
2. how do we identify those genes that have undergone
cancer-promoting changes among all the other genes in the
cancerous cells?
a) cancer depends on a whole set of mutations and epigenetic changes
b) a cancer cell contains a large number of somatic mutations that are
accidental by-products
c) many of the genes that are repeatedly altered in human cancers
(cancer-critical genes)
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Cancer-critical genes are grouped into two broad
classes, based on whether the cancer risk arises from too
much activity of the gene product or too little.
1. Genes with a gain-of-function mutation:
can drive a cell toward cancer, are called proto-oncogenes; their
mutant, overactive or overexpressed forms are called oncogenes.
2. Genes with a loss-of-function mutation
can contribute to cancer, are called tumor suppressor genes.
• In both cases, the mutation may lead toward cancer
a) directly by causing cells to proliferate when they should not
b) Indirectly by causing genetic or epigenetic instability and so hastening
the occurrence of other inherited changes that directly stimulate
tumor growth. Those genes whose alteration results in genomic
instability represent a subclass of cancer-critical genes that are
sometimes called genome maintenance genes.

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mutations in oncogenes and tumor suppressor genes can have
similar effects in promoting the development of cancer
• overproduction of a signal for cell proliferation can result from
either kind of mutation.
• Thus, from the point of view of a cancer cell, oncogenes and
tumor suppressor genes—and the mutations that affect
them—are flip sides of the same coin.

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Cancer-critical mutations fall into
two readily distinguishable
categories, dominant and
recessive.

A) Oncogenes act in a dominant manner:

a gain-of-function mutation in a single
copy of the cancer-critical gene can drive
a cell toward cancer.

(B) Mutations in tumor suppressor

genes, on the other hand, generally act
in a recessive manner: the function of
both alleles of the cancer- critical gene
must be lost to drive a cell toward
cancer.

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Retroviruses Led to the Identification of Oncogenes
(Francis Peyton Rous, Nobel Prize in 1966)
• One of the first animal viruses to be implicated in cancer was discovered in
chickens more than 100 years ago, when an infectious agent that causes
connective-tissue tumors, or sarcomas, was identified as a virus—the Rous
sarcoma virus.
• When it infects a cell, its RNA genome is copied into DNA by reverse
transcription, and the DNA is inserted into the host genome, where it can persist
and be inherited by subsequent generations of cells.
• What was inserted by the Rous sarcoma virus to make the host cells cancerous?
• It was a piece of DNA that was unnecessary for the virus’s own survival or reproduction;
instead, it was a passenger, a gene called v-Src, that the virus had picked up on its travels.
• v-Src was similar, but not identical, to a gene—c-Src—that is found in all vertebrate
genomes and encodes a protein tyrosine kinase.
• c-Src had evidently been taken up accidentally by the retrovirus from the genome of a
previously infected host cell, and it had undergone mutation in the process to become an
oncogene (v-Src).

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Other viral oncogenes carried by retroviruses
that cause cancer in nonhuman animals.
•Each such oncogene has a counterpart
proto-oncogene in the normal vertebrate genome.
•As was the case for Src, these other oncogenes
generally differed from their normal counterparts,
either in structure or in level of expression.

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Identification of human oncogenes
1. DNA was extracted from human tumor cells
2. broken into fragments, and
3. introduced into cultured mouse cells.
Result:
• Occasional colonies of abnormally proliferating cells began to appear in the
culture dish that showed a transformed phenotype, outgrowing the
untransformed cells in the culture and piling up in layer upon layer.
• Each colony was a clone originating from a single cell that had incorporated a
DNA fragment that drove cancerous behavior.
• Once isolated and sequenced, the DNA fragments were found to contain a
human version of a gene already known from study of a retrovirus that
caused tumors in rats—an oncogene called v-Ras.
• The newly discovered oncogene was clearly derived by mutation from a
normal human gene, one of a small family of proto-oncogenes called Ras.

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Ras genes are among the most important of
all cancer-critical genes
• Normal Ras proteins are monomeric GTPases that help
transmit signals from cell-surface receptors to the cell interior.
• The Ras oncogenes isolated from human tumors contain point
mutations that create a hyperactive Ras protein that cannot shut
itself off by hydrolyzing its bound GTP to GDP.
• Because this makes the protein hyperactive, its effect is
dominant; that is, only one of the cell’s two gene copies needs
to change to have an effect.
• One or another of the three human Ras family members is
mutated in about 30% of all human cancers.
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Genes Mutated in Cancer Can Be Made Overactive
in Many Ways

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Genes Mutated in Cancer Can Be Made
Overactive in Many Ways
(1) A small change in DNA sequence such as a point mutation or deletion may
produce a hyperactive protein when it occurs within a protein-coding sequence or
lead to protein overproduction when it occurs within a regulatory region for that
gene.
(2) Gene amplification events, such as those that can be caused by errors in DNA
replication, may produce extra gene copies; this can lead to overproduction of the
protein.
(3) A chromosomal rearrangement— involving the breakage and rejoining of the
DNA helix—may either change the protein-coding region, resulting in a hyperactive
fusion protein, or alter the con- trol regions for a gene so that a normal protein is
overproduced.

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 Mutation of the epidermal growth factor (EGF) receptor can make it
active even in the absence of EGF, and consequently oncogenic.

• Normally, binding of EGF to the

receptor’s extracellular domain
leads to phosphorylation of the
intracellular domain, which
activates signaling.
• Truncation of the extracellular
domain leads to
hyperphosphorylation and
inappropriate activation. Other
types of activating mutations are
observed in different cancers. like a faulty
doorbell that rings
even when nobody
is pressing the
button
How would you identify a
gene that has been inactivated
in the genome of a cancer
cell?

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• one cannot use a cell transformation assay to identify
something that simply is not there.

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Discovery of the first tumor suppressor gene came from
studies of a rare type of human cancer, retinoblastoma
• Retinoblastoma occurs in childhood, and tumors develop from neural precursor cells in
the immature retina.
• About one child in 20,000 is afflicted.
• One form of the disease is hereditary, and the other is not.
• In the hereditary form, multiple tumors usually arise independently, affecting both eyes
• in the nonhereditary form, only one eye is affected, and by only one tumor.
• A few individuals with retinoblastoma have a visibly abnormal karyotype, with a deletion of
a specific band on chromosome 13 that, if inherited, predisposes an individual to the
disease. Deletions of this same region are also encountered in tumor cells from some
patients with the nonhereditary disease, which suggested that the cancer was caused by
loss of a critical gene in that location.

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By mapping the location of this chromosomal
deletion, it was possible to identify the Rb gene.
• In the hereditary form, a deletion or loss-of-function mutation
was present in one copy of the Rb gene in every somatic cell.
• These cells are predisposed to becoming cancerous but do not
do so if they retain one good copy of the gene.
• The retinal cells that are cancerous are defective in both copies
of Rb because of a somatic event that has eliminated the
function of the previously good copy.

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In the nonhereditary form of the disease, the noncancerous
cells show no defect in either copy of Rb, while the
cancerous cells have become defective in both copies.
These nonhereditary retinoblastomas are very rare because
they require two independent events that inactivate the
same gene on two chromosomes in a single retinal cell
lineage

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The genetic mechanisms that cause retinoblastoma.

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Both Genetic and Epigenetic Mechanisms
Can Inactivate Tumor Suppressor Genes
• Inactivation of tumor suppressor genes is dangerous. This inactivation can occur in
many ways, with different combinations of mishaps serving to eliminate or cripple
both gene copies.
1. The first copy may be lost by a small chromosomal deletion or inactivated by a
point mutation due to a random error in DNA replication.
2. The second copy is more commonly eliminated by a less specific mechanism
that is likely to occur in cells progressing toward cancer that have become
genetically unstable. The chromosome carrying the remaining normal copy may
be lost from the cell or damaged
a) due to errors in chromosome segregation or
b) the normal gene may be replaced by a mutant version through either a mitotic
recombination event or a gene conversion that accompanies it.
3. Epigenetic changes can permanently inactivate a tumor suppressor gene. Most
commonly, the C nucleotides in CG sequences in its promoter may become
methylated in a heritable manner, which can irreversibly silence the gene in a
cell and in all of its progeny

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Six ways of inactivating the remaining good copy of a tumor suppressor gene through changes in
DNA sequence or an epigenetic mechanism

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Systematic Sequencing of Cancer Cell Genomes Has
Transformed Our Understanding of the Disease

This Photo by Unknown Author is licensed under CC

BY

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Cancer cell genomes can be scanned
systematically in several different ways
1. At one extreme—the most costly, but no longer prohibitively so—one can determine a
tumor’s complete genome sequence.
2. More cheaply, one can focus just on the 21,000 or so genes in the human genome that
code for protein (the so-called exome), looking for mutations in the cancer cell DNA that
alter the amino acid sequence of the product or prevent its synthesis
3. survey of the genome for regions that have undergone deletion or duplication to reveal
copy number variations and the loss or gain of chromosomes (aneuploidy).
4. The genome can also be scanned for epigenetic changes to reveal changes in
methylation patterns of DNA or other changes that accompany transcriptional silencing or
activation without affecting DNA sequence.
5. Systematic sequencing of RNAs can reveal alterations in levels of gene expression by
analysis of mRNAs, as well as levels of regulatory noncoding RNAs.
6. measure the expression of known cancer- critical genes directly by detecting their protein
products, tumor cell lysates can be surveyed quantitatively using mass spectrometry.

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Many Cancers Have an Extraordinarily Disrupted Genome

• Gross genetic disruption in cancer cells is common.

• This varies greatly among cancer types and from one cancer patient
to another, both in severity and in character.
1. the chromosomal karyotype may appear normal
numerous point mutations in individual genes due to a failure of the repair
mechanisms that normally correct errors in the replication or maintenance of
DNA sequences.
2. the karyotype is extremely disrupted
many chromosomal breaks and rearrangements
chromosome sequences are completely scrambled, indicating that extensive
fragmentation of the DNA occurred followed by random re-assembly.
3. Aneuploidy [a change in chromosome karyotype from the normal
number (46)] is a common feature in human cancers.

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Epigenetic and Chromatin Changes Contribute
to Most Cancers
• changes that modify gene expression epigenetically, without altering the DNA
sequence.
• increased methylation of DNA in the promoter region of a gene such as Rb can
permanently silence it.
• reversible covalent modifications such as methylation and acetylation also occur
on the histone proteins that package DNA into chromatin.
• histone marks modulate gene expression by altering the conformation and
accessibility of chromatin to regulatory factors such as transcription factors and
chromatin remodeling complexes

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Epigenetic and genetic
mechanisms can cooperate to
promote the evolution of cancer

• Both genetic mutations and

environmental factors (such as
metabolic state) can lead to epigenetic
changes.
• these epigenetic changes can in turn
increase the rate at which genetic as
well as further epigenetic changes
accumulate—thereby speeding the
process of cancer progression by
altering gene expression in ways that
promote cancer cell proliferation and
are inherited in clones of cells.

60
Among the many somatic mutations
identified in cancer cells, how can we
discover which of them are drivers of
cancer

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✔Frequency of occurrence of a mutation
✔By compiling the genome sequence data for
different types of cancer, each with its own set of
identified driver mutations, we can develop a
comprehensive catalog of those genes that are
strongly suspected to be cancer-critical for at
least one type of tumor.

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Disruptions in a Handful of Key Pathways
Are Common to Many Cancers
These two genes control fundamental processes of cell division
and growth
1. Rb
2. Ras
• Mutations in these 2 genes are found many cases of cancer and
in cancers of many different types.

63
In many cases of cancer, Rb is intact or Ras is
not mutated
• What part do mutations in the hundreds of other cancer-critical
genes play in the development of the disease?
✔ With our increasing knowledge of the normal functions of the genes in
the human genome, it is becoming easier to detect patterns in the
cataloged driver mutations and to give some simplifying answers to
these questions.

64
 The three major cellular pathways that contribute to tumorigenesis

Rb pathway governs initiation

of the cell-division cycle

Ras (RTK/Ras/PI 3-kinase) pathway, serves

to transmit signals for cell growth and cell
division from outside the cell to the cell
interior.
p53 pathway regulates
responses to stress and DNA
damage
these three fundamental controls are subverted in one way or another in virtually every type of cancer.
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Mutations in the PI 3-kinase/Akt/mTOR
Pathway Drive Cancer Cells to Grow
• the PI 3-kinase/Akt/mTOR intracellular signaling pathway is
critical for cell growth control.
• various extracellular signal proteins (e.g., insulin and insulin-like
growth factors) normally activate this pathway.
• In cancer cells, the pathway is activated by mutation so that the
cell can grow in the absence of such signals.
• Abnormal activation
stimulates protein synthesis
increases both glucose uptake and the production of the acetyl CoA in
the cytosol required for cell lipid synthesis

66
Mutations in the PI 3-kinase/Akt/mTOR Pathway Drive Cancer Cells to Grow
a) In order to multiply successfully, most normal cells
require extracellular signals that drive
1) cell-cycle progression (mitogen) and
2) extracellular signals that drive cell growth
(growth factor).
b) Activation of Akt and mTOR
drives cell growth through greatly stimulating
glucose uptake and utilization, including a
conversion of the excess citric acid produced
from sugar intermediates in mitochondria into
the acetyl CoA that is needed in the cytosol for
lipid synthesis and new membrane production.
Protein synthesis is also increased.
This system becomes abnormally activated early in
tumor progression. TCA cycle indicates the
tricarboxylic acid cycle (citric acid cycle).

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Mitogen stimulation of cell- cycle entry

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Mitogen stimulation of cell- cycle entry
• mitogens bind to cell-surface receptors to initiate intracellular signaling
pathways.
activation of the small GTPase Ras> activates a MAP kinase cascade>
leads to increased expression of numerous immediate early genes,
including the gene encoding the transcription regulatory protein Myc.
Myc increases the expression of many delayed- response genes, including
some that lead to increased G1-Cdk activity (cyclin D– Cdk4),> triggers the
phosphorylation of members of the Rb family of proteins. This inactivates
the Rb proteins, freeing the gene regulatory protein E2F to activate
the transcription of G1/S genes, including the genes for a G1/S-cyclin
(cyclin E) and S-cyclin (cyclin A). The resulting G1/S-Cdk and S-Cdk
activities further enhance Rb protein phosphorylation, forming a positive
feedback loop. E2F proteins also stimulate the transcription of their own
genes, forming another positive feedback loop.

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Mutations in the p53 Pathway Enable
Cancer Cells to Survive and
Proliferate Despite Stress and DNA
Damage

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What is the normal function of p53 pathway?
• most cells in the body contain very little p53 protein under
normal conditions: although the protein is synthesized, it is
rapidly degraded.
• Mice in which both copies of the gene have been deleted or
inactivated typically appear normal in all respects except
one—they universally develop cancer before 10 months of age.
• These suggest that p53 has a function that is required only in
special circumstances.

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Cells raise their concentration of p53 protein in
response to a number of conditions that put the cell
in danger of death or serious injury
✔ DNA damage
✔ telomere loss or shortening
✔ Hypoxia
✔ osmotic stress
✔ oxidative stress
✔ when regulatory signals are intense or uncoordinated

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 Modes of action of the p53 tumor suppressor

• The p53 protein is a cellular stress sensor.

• In response to hyperproliferative signals, DNA
damage, hypoxia, telomere shortening, and various
other stresses, the p53 levels in the cell rise.
• this may either arrest cell cycling in a way that allows
the cell to
adjust and survive
trigger cell suicide by apoptosis, or
cause cell senescence—an irreversible cell-cycle
arrest that stops damaged cells from dividing.

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Epidemiology Reveals That Many Cases of
Cancer Are Preventable

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Sensitive Assays Can Detect Cancer-causing
Agents That Damage DNA

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 Test for mutagenicity
• the carcinogen is mixed with an activating extract prepared from
rat liver cells (to mimic the biochemical processing that occurs
in an intact animal).
• The mixture is then added to a culture of specially designed test
bacteria and the bacterial mutation rate measured.
• Most of the compounds scored as mutagenic by this rapid and
convenient assay in bacteria also cause mutations or
chromosome aberrations when tested on mammalian cells.

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77
Viruses and Other Infections Contribute to a
Significant Proportion of Human Cancers

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Infectious Agents Can Cause Cancer in a
Variety of Ways
• In papillomaviruses,
the viral genes that are mainly to blame are called E6 and E7.
The protein products of these viral oncogenes interact with many host-cell proteins> they
bind to two host proteins proteins (Rb and p53)
• Other DNA tumor viruses use similar mechanisms to inhibit Rb and p53
• Some viruses have indirect tumor-promoting actions.
• The hepatitis-B and hepatitis-C viruses favor the development of liver cancer by causing
chronic inflammation (hepatitis), which stimulates extensive cell division in the liver that
promotes the eventual evolution of tumor cells.
• In AIDS, the human immunodeficiency virus (HIV) promotes development of an otherwise
rare cancer called Kaposi’s sarcoma by destroying the immune system, thereby permitting a
secondary infection with a human herpesvirus (HHV-8) that has a direct carcinogenic action.
• By causing severe inflammation, chronic infection with parasites and bacteria can also
promote the development of some cancers. For example, chronic infection of the stomach
with the bacterium Helicobacter pylori, which causes ulcers, appears to be a major cause of
stomach cancer; dramatic falls in the incidence of stomach cancer over the past half-century
correlate with a decline in the incidence of Helicobacter infections.

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The Search for Cancer Cures Is Difficult but
Not Hopeless
• Ionizing radiation and most anticancer drugs damage DNA or interfere with chromosome
segregation at mitosis, and they preferentially kill cancer cells because cancer cells have a
diminished ability to survive the damage.
• Normal cells treated with radiation arrest their cell cycle until they have repaired the
damage to their DNA.
• Because cancer cells generally have defects in their checkpoint responses, they may
continue to divide after irradiation, only to die after a few days because the genetic damage
remains unrepaired.
• More generally, most cancer cells are physiologically deranged to a stressful degree: they
live dangerously. Even though the cells in a tumor have evolved to be unusually tolerant of
minor DNA damage, they are hypersensitive to the much greater amount of damage that
can be created by radiation and by DNA-damaging drugs. A small increase of genetic
damage can be enough to tip the balance between proliferation and death. Unfortunately,
however, DNA-damaging therapies typically cause terrible side effects on normal, rapidly
dividing cells in the digestive system, bone marrow, and mucous mem- branes.
Furthermore, these treatments are themselves carcinogenic and can lead to second
cancers.

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