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LECTURE 11
QUIZ #5
15 minutes

When Development goes wrong: Cancer

Please write your name on the quiz

Please write your section on the quiz

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Image by Gopal Murti/Visuals Unlimited, Inc.

The relationship between apoptosis and disease

Learning Goals
Recognize that cancer is a disease caused by our own genes
Understand how scientists discovered the causes of cancer
Recognize the difference between oncogenes and tumor
suppressors
Appreciate the action of carcinogens in mutating or rearranging
the DNA
See the link between developmental genes and cancer genes

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The main causes of death in the U.S.

What are some of the differences now as compared

to ~100 years ago?

Cancer is the uncontrolled proliferation/

division of cells or loss of cell death
Cancer is a collection
of diseases.
Leukemias
Sarcomas
Carcinomas

Cancer is caused by genetic changes to our cells

Normal blood

Blood from chronic myelogenous leukemia

Cancer cells form large

masses of themselves,
tumors.

Lung squamous cell carcinoma

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Cancer is caused by changes to our genes

Normal cells can become transformed

carcinogen

Normal cells exhibiting

contact inhibition

Transformed cells

Photos: G. Steven Martin

stop undergoing mitosis

lose ability to undergo contact inhibition

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47,000 mutations found in a lung cancer

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DNA damage causes cancer by mutating the

genes that control cell division and survival
Oncogenes are required for cell
division (gas)
Proto-oncogenes

Tumor Suppressors are required to

stop cell division (brakes)
Somatic mutations: Mutation occurs in cells of the body.
Govindan, et al. (2012) Cell 150: 1121-1134.

Germ line mutations: Mutation occurs in the germ cells.

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Breakthrough in our understanding of

cancer came from studying viruses

HPV-associated cervical cancer

killed Henrietta Lacks (HeLa)

Human cancer-causing viruses

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Rous Sarcoma Virus

How do you think he proved it was a virus?

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Rous P.. (1911) A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med.13:397

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Rous sarcoma virus contains 4 genes

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RAS was the first known mutated

human oncogene

Two ways viruses

cause tumors
1. Incorporates a protooncogene into its viral
genome.
2. Insert next to proto-oncogene
in host DNA.

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1976 Nature Publishing Group

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RAS pathway

Humans and mice have 3 RAS genes

HRAS
NRAS
KRAS

- All can be mutated to a gain-of-function via missense mutation at GLY12.

- This renders the GTPase domain of Ras insensitive to inactivation,
locking the protein in an active, GTP-bound "on state".
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KRAS gain of function (activated RAS) is

sufficient to cause cancer in a mouse

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KRAS is an essential gene

Comparison of Kras / embryos and control littermates.

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Parikh N et al. Mol Cancer Res 2012;10:845-855

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The normal function of proto-oncogenes is

to control cell growth and proliferation.

Famous oncogenes
ERB
RAS
SRC
ABL
BCL2
MYC 25

Chromosome abnormalities in cancer cells

Chromosome painting (spectral karyotyping) reveals multiple
translocations in this promyelocytic leukemia patient

Some
chromosomal
translocations
move a gene
upstream of
another genes
enhancer element
In Burkitt lymphoma, Myc, which is
normally found on chromosome 8,
is transferred to chromosome 14.
This is known as a chromosome
translocation; such changes can be
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characteristic of particular cancers.

Tumor suppressors
Checkpoints prevent inappropriate proliferation.
Disruption of both copies of a tumor suppressor leads to
cancer
In contrast, only one allele of an oncogene needs to be
activated.

Rb
Normal

PML

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Retinoblastoma : Knudson's hypothesis

Sporadic
Late onset
Single tumor
Limited

Familial
Early onset
Multiple Tumors
Secondary Tumors

Inherit two normal genes

Lose one - a rare event
Lose other
Tumor

Inherit one normal/one defective

Lose normal one
Tumor

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Knudsons two hit hypothesis

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Tumor suppressors come in many different flavors

Famous tumor suppressors

Rb and P53 are the most frequently mutated genes in human
cancers.
P53 encodes the p53 protein that responds to DNA damage.
Upon sensing DNA damage, p53 is activated, resulting in
either G1 cell cycle arrest or apoptosis.
PTEN encodes a phosphatase that inhibits kinase signaling.
BRCA1 and BRCA2 encode DNA binding proteins required
for DNA damage repair.
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Metastasis

Cancer is a multistep process

Loss of APC

Activation of ras

Loss of DCC

Loss of p53

Other mutations

Other mutations

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Endostatin, an angiogenesis inhibitor can

cure certain solid cancers

Angiogenesis

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Why has cancer been so tough to eradicate

Cancer is a disease of our own cells and genes that have
become altered in some way.

Treating
Cancer
Diseases

Because these cells look and behave like our cells, there is no
plethora of foreign antigens for our immune system to
recognize.
Drugs that kill tumor cells also kill our normal cells.
There are hundreds of different cancers.

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Key concepts

Targeted therapies based on

personalized medicine

Cancer is a disease of our own genes and cells.

Carcinogens are compounds that cause cancer by mutating
our genes.
Proto-oncogenes normally promote cell division and get
activated to act as oncogenes in cancer.
Tumor suppressor genes normally act to prevent cell division.
Both copies are lost/deleted in cancer.
Cancer usually requires activation of oncogenes and loss of
tumor suppressors in the same cell.
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Class exercise on breast

cancer susceptibility
Inherited breast cancer susceptibility (BRCA)
Women who inherit a mutant BRCA1 gene
have a 66% chance of breast cancer or
ovarian cancer by age 55.

Is susceptibility dominant or
recessive?
Penetrance:
Expressivity:

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BRCA1 mutations

BRCA1 associated cancers: Usually inheritance of a mutant copy

and then subsequent deletion/mutation of the remaining copy.
Whats the resemblance to the Knudsons retinoblastoma example?
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From Biology: How Life Works

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BRCA1 and BRCA2 are both

essential genes

Hypothetical BRCA1 family

From Biology: How Life Works

Why no BRCA1 mutant homozygotes?

Why do some daughters carry the mutant BRCA1 but not get
affected?
Why do some daughters not carrying the mutant BRCA1 still get
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affected?

BRCA1 and BRCA2 proteins act in a

complex to repair damaged DNA

Brca1 +/+

Brca2 +/+

Brca1 -/-

Brca2 -/-

The Brca1 and Brca2 loss of function mutant phenotype is almost identical.
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What does that say about the normal function of these 2 genes?

Key concepts
Cancer is a disease of our own genes and cells.
Carcinogens are compounds that cause cancer by mutating
our genes.
Proto-oncogenes normally promote cell division and get
activated to act as oncogenes in cancer.
Tumor suppressor genes normally act to prevent cell division,
or repair DNA damage. Both copies are lost/deleted in cancer.
Cancer usually requires activation of oncogenes and loss of
tumor suppressors in the same cell.
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