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8/18/2019 BIO 103 Lecture 11
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QUIZ #5
15 minutes
Please write your name on the quiz
Please write your section on the quiz
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LECTURE 11
Image by Gopal Murti/Visuals Unlimited, Inc.
When Development goes wrong: Cancer
Learning Goals
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Recognize that cancer is a disease caused by our own genes
• Understand how scientists discovered the causes of cancer
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Recognize the difference between oncogenes and tumorsuppressors
• Appreciate the action of carcinogens in mutating or rearranging
the DNA
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See the link between developmental genes and cancer genes
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The relationship between apoptosis and disease
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The main causes of death in the U.S.
What are some of the differences now as comparedto ~100 years ago?
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Cancer is the uncontrolled proliferation/
division of cells or loss of cell death
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Cancer is a collection
of diseases.
– Leukemias
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Sarcomas –
Carcinomas
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Cancer cells form large
masses of themselves,
tumors.
Lung squamous cell carcinoma
Blood from chronic myelogenous leukemia
Normal blood
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Cancer is caused by genetic changes to our cells
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Photos: G. Steven Martin
Normal cells can become transformed
Normal cells exhibiting
contact inhibitionTransformed cells
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Cancer is caused by changes to our genes
carcinogen
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47,000 mutations found in a lung cancer
Govindan, et al. (2012) Cell 150: 1121-1134.12
DNA damage causes cancer by mutating the
genes that control cell division and survival
Somatic mutations: Mutation occurs in cells of the body.
Germ line mutations: Mutation occurs in the germ cells.
Oncogenes are required for celldivision (gas)
Tumor Suppressors are required tostop cell division (brakes)
stop undergoing mitosis ose ability to undergo contact inhibition
Proto-oncogenes
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Breakthrough in our understanding of
cancer came from studying viruses
Human cancer-causing viruses
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HPV-associated cervical cancer
killed Henrietta Lacks (HeLa)
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Rous Sarcoma Virus
Rous P.. (1911) A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med.13:397
How do you think he proved it was a virus?
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Rous sarcoma virus contains 4 genes
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Two ways viruses
cause tumors
1.
Incorporates a proto-oncogene into its viral
genome.
2. Insert next to proto-oncogene
in host DNA.
© NaturePublishing Group1976
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RAS was the first known mutated
human oncogene
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RAS pathway
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• HRAS
• NRAS
• KRAS
Humans and mice have 3 RAS genes
- 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
Parikh N et al. Mol Cancer Res 2012;10:845-855
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KRAS is an essential gene
!Comparison of Kras "/" embryos and control littermates.
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The normal function of proto-oncogenes is
to control cell growth and proliferation.
Famous oncogenesERB
RAS
SRC
ABL
BCL2MYC
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Some
chromosomal
translocationsmove a gene
upstream of
another gene’s
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
characteristic of particular cancers.
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Chromosome abnormalities in cancer cells
Chromosome painting (spectral karyotyping) reveals multipletranslocations in this promyelocytic leukemia patient
Normal PML 28
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
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Retinoblastoma : Knudson's hypothesis
Sporadic Familial
Late onset Early onsetSingle tumor Multiple Tumors
Limited Secondary Tumors
Inherit two normal genes Inherit one normal/one defective
Lose one - a rare event Lose normal one
Lose other Tumor
Tumor
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Knudson’s two hit hypothesis
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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 ineither G1 cell cycle arrest or apoptosis.
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PTEN encodes a phosphatase that inhibits kinase signaling.
• BRCA1 and BRCA2 encode DNA binding proteins requiredfor DNA damage repair.
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Tumor suppressors come in many different flavors
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Loss of APC
Activation of ras
Loss of DCC
Loss of p53
Other mutations
Other mutations
Cancer is a multistep process
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Metastasis
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Angiogenesis
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Endostatin, an angiogenesis inhibitor can
cure certain solid cancers
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Why has cancer been so tough to eradicate
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Cancer is a disease of our own cells and genes that have
become altered in some way.
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Because these cells look and behave like our cells, there is no
plethora of foreign antigens for our immune system to
recognize.
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Drugs that kill tumor cells also kill our normal cells.
• There are hundreds of different cancers.
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Treating
Cancer
Diseases
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Targeted therapies based on
personalized medicine
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Key concepts
• Cancer is a disease of our own genes and cells.
• Carcinogens are compounds that cause cancer by mutatingour genes.
•
Proto-oncogenes normally promote cell division and getactivated to act as oncogenes in cancer.
• Tumor suppressor genes normally act to prevent cell division.
Both copies are lost/deleted in cancer.
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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.
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Is susceptibility dominant orrecessive?
Penetrance:
Expressivity:
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From Biology: How Life Works
BRCA1 associated cancers: Usually inheritance of a mutant copyand then subsequent deletion/mutation of the remaining copy.
What’s the resemblance to the Knudson’s retinoblastoma example?44
BRCA1 mutations
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Hypothetical BRCA1 family
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
affected?
From Biology: How Life Works
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BRCA1 and BRCA2 are both
essential genes
Brca2 +/+ Brca2 -/-
Brca1 +/+ Brca1 -/-
The Brca1 and Brca2 loss of function mutant phenotype is almost identical.
What does that say about the normal function of these 2 genes?
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BRCA1 and BRCA2 proteins act in a
complex to repair damaged DNA
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Key concepts
• Cancer is a disease of our own genes and cells.
• Carcinogens are compounds that cause cancer by mutatingour genes.
•
Proto-oncogenes normally promote cell division and getactivated 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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