Cancer in the media

Cancer of the breast, colon, prostate, and many

other sites in the body are being connected to
specific genes... But the meaning of this isn't
always clear.
•What does it mean for you if your mother has or had
breast cancer... or an aunt and two cousins have colon
cancer?
•What does it mean for your children if you've been
diagnosed with cancer of the endocrine glands or some
other organ?
cancer is a disease of the
cell cycle
 Cell Cycle Checkpoints
Spindle
Apoptosis Assembly
Checkpoint Checkpoint
Mitosis
P M
G2
A
assembly of T
DNA Damage components
Checkpoints for division cytokinesis

S G1
chromosomes cytoplasm
replicate doubles

DNA Damage
Checkpoint
 Normal cells vs. Cancer
cells
Normal cell proliferation Cancer cell proliferat
Anchorage dependent Anchorage independe
Density-dependent Can grow on top of on
inhibition another
Limited number of cell Immortal
divisions
Telomere shortening Telomere maintenanc
Proliferation dependent Constant signal to
upon extracellular divide
signals independent
Checkpoints activated at Loss of checkpoint
appropriate times
Apoptosis functional Apoptosis inhibited
 How do we define cancer?

Cancer is a group of disorders that causes

cells to escape normal controls on cell
division

-cancer cells divide more frequently

-cancer cells are not inhibited by contact with
other cells and can form tumors
-cancer cells can invade other tissues, i.e.
metastasis
 Cancer cells
grow into tumors.

Non-cancerous
cells form sheets. Cancer cells can
invade other tissues.
 Control of the Cell
Cycle

Mechanisms for controlling progress

through the cell cycle:
Checkpoints
Length of Telomeres
Chemical Signals from within and
outside the cell
Length of Telomeres

telomeres

Telomeres are
structures at the ends
of chromosomes that
shorten with each cell
division. After 50
divisions, the shortened
length of telomeres
causes mitosis to stop.
 Failure to Stop at
Cell Cycle Checkpoints

Mutation in a gene that Rate of cell division is

usually slows the cell accelerated.
cycle
Failure to pause for Faulty DNA leads to
DNA repair unregulated cell growth.

Loss of control over Cancer cells have

telomere length telomerase, an enzyme
that elongates telomeres.
Cells continue to divide
after 50 mitoses.
Chemical Signals that Control the
Cell Cycle
1. Cyclin and Kinase
-proteins that initiate mitosis
-requires buildup of cyclin to pair with kinase
2. Hormones
-chemical signals from specialized glands
that stimulate mitosis
3. Growth Factors
-chemical factors produced locally that stimulate
mitosis
 Caspase
Apoptosis: Cell enzymes carry
out cell
Death destruction
Signal arrives at
“death” receptor
on cell

White blood
cells destroy cell
fragments
 Cell Cycle Checkpoints

 Transitions between different phases of the

cell cycle (G1, S, G2, and M) are regulated at
checkpoints.

 A checkpoint is a mechanism that halts

progression through the cycle until a critical
process is completed.

© John Wiley & Sons, Inc.

 Cyclins and CDKs
 Important checkpoint proteins are the cyclins and the
cyclin-dependent kinases (CDKs); complexes formed
between cyclins and CDKs cause the cell cycle to
advance.

 The CDKs phosphorylate target proteins but are

inactive unless they are associated with a cyclin
protein.

 Cell cycling requires the alternate formation and

degradation of cyclin/CDK complexes.

© John Wiley & Sons, Inc.

Checkpoints in Tumor Cells
 In tumor cells, cell cycle checkpoints are often
deregulated due to genetic defects in the machinery
that alternately raises and lowers the abundance of
the cyclin/CDK complexes.

 These mutations may be:

 in the genes encoding the cyclins or CDKs,
 in genes encoding the proteins that respond to specific
cyclin/CDK complexes
 in genes encoding proteins that regulate the
abundance of these complexes.

© John Wiley & Sons, Inc.

Cancer and Programmed Cell Death
 Apoptosis is part of the normal developmental
program in animals and is important in the prevention
of cancer.

 The caspases, a family of proteolytic enzymes, are

involved in apoptosis and cleave many target proteins.

 If apoptosis is impaired, a cell that should be killed can

survive and proliferate, potentially forming a clone
that could become cancerous.

© John Wiley & Sons, Inc.

 Evidence of a Genetic Basis for
Cancer
 The cancerous state is clonally inherited.

 Some types of viruses can induce the formation of

tumors in experimental animals.

 Cancer can be induced by mutagens.

 Certain types of white blood cell cancers are

associated with particular chromosomal
abnormalities.

© John Wiley & Sons, Inc.

 Cancer and Genes
 Oncogenes are genes that, when mutated,
actively promote cell proliferation. By:
 … the overexpression of certain genes
 …the abnormal activity of certain genes
 …their mutant protein products.

 Tumor suppressor genes are genes that, when

mutated, fail to repress cell division.
Proto-Oncogenes
 The proteins encoded by viral oncogenes are
similar to cellular proteins with important
regulatory functions.

 These cellular homologues are called proto-

oncogenes or normal cellular genes.

 The normal c-oncogenes have introns; the viral v-

oncogenes often lack introns.

 From c-onco to v-onco….. Replication-

defective viruses
 Cancer is the Result of
Several Mutations
 A single mutation usually does not result in
cancer.

 Usually several genes that regulate cell

growth are mutated before a cancerous
state results.
Knudson’s Two-Hit
Hypothesis
 When tumor suppressor genes are mutated, a
predisposition to develop cancer often follows
a dominant pattern of inheritance.

 The mutation is usually a loss-of-function

mutation in the tumor suppressor gene.

 Cancer develops only if a second mutation in

somatic cells knocks out the function of the
wild-type allele.
© John Wiley & Sons, Inc.
 Cellular Roles of Tumor Suppressor
Proteins
 The proteins encoded by tumor suppressor
genes are involved in
 cell division,
 cell differentiation,
 programmed cell death,
 DNA repair.
p53 Regulates Cell Cycle and
Apoptosis
 The p53 tumor suppressor protein is encoded
by the TP53 gene (53 KDa).

 Inherited mutations in TP53 are associated

with Li-Fraumeni syndrome.

 Somatic mutations that inactivate both copies

of TP53 are associated with the majority of
cancers.
Tumour suppressor genes
 The gene’s normal function is to regulate
cell division. Both alleles need to be
mutated or removed in order to lose the
gene activity.
 The first mutation may be inherited or
somatic.
 The second mutation will often be a gross
event leading to loss of heterozygosity in
the surrounding area.
The Cellular Function of
p53 Expression
p53 of p53 is very low in normal cells.

 Expression of p53 increases in response to

DNA damage due to a decrease in
degradation.

 p53 can inhibit cell division or induce apoptosis.

Therefore p53
 suppresses progression through the cell
cycle in response to DNA damage
 initiates apoptosis if the damage to the
cell is severe
 acts as a tumour suppressor
 is a transcription factor and once
activated, it represses transcription of
one set of genes (several of which are
involved in stimulating cell growth)
while stimulating expression of other
genes involved in cell cycle control
pBRCA1 and pBRCA2 regulate DNA
repair.
 Mutations in the tumor suppressor genes
BRCA1 (Ch17) and BRCA2 (Ch13) have been
implicated in hereditary breast and ovarian
cancer.

 Both genes encode proteins that are localized

in the nucleus and have putative
transcriptional activation domains.

 pBRCA1 and pBRCA2 may be involved in DNA

repair in human cells.
 Breast Cancer

“Why do so many of my relatives have breast cancer...is this just plain bad luck or
what?”
 breast cancer
Within the general population,
there is an 11% chance that any
woman will develop breast cancer
over her lifetime. For any one
individual, this risk may be
increased or decreased by a variety
of factors:
 her age, family history,
 age at which she began menstruating,
 whether she has given birth and her age at the
time of the first birth, and
 whether or not a breast biopsy was performed in
the past.
 Hallmarks of Pathways to Malignant
Cancer
1. Cancer cells acquire self-sufficiency in the
signaling processes that stimulate division and
growth.
2. Cancer cells are abnormally insensitive to
signals that inhibit growth.
3. Cancer cells can evade programmed cell death
(apoptosis).
4. Cancer cells acquire limitless replicate potential.
5. Cancer cells develop ways to grow themselves.
6. Cancer cells acquire the ability to invade other
tissues and colonize them
Types of genes which may mutate
to cause cancer:

 Tumour suppressor genes

 oncogenes
 DNA repair genes
 telomerase
 p53
 The environment:
Some environmental agents associated with cancer
are:
 Viruses
 Tobacco smoke
 Food
 Radiation
 Chemicals
 Pollution
 oncogenes
 Cellular oncogene c-onc
 Viral oncogene v-onc
 Proto-oncogene, activated by
mutation to c-onc
Types of proto-oncogene

 G proteins
e.g. Ras (Rat sarcoma)
Types of proto-oncogene

 Nuclear transcription factors

e.g. MYC (myelocyto matosis virus)
Transformation
is a multistep
process
Transformation is a multistep
process
Colorectal Cancer

 11% of cancer-
related deaths
 Tumor progression
may take 10-35 years
 Adenomatous polyp
develops into
carcinoma