dr mohamed fakhry 2015 1 molecular basis of cancer
TRANSCRIPT
Dr MOHAMED FAKHRY 20151
MOLECULAR BASIS OF CANCER
Cellular Basis of Cancer Cancer is a collection of diseases
characterized by abnormal and uncontrolled growth
Cancer arises from a loss of normal growth control
In normal tissues, the rates of new cell growth and old cell death are kept in balance
In cancer, this balance is disrupted
This disruption can result from1) uncontrolled cell growth or2) loss of a cell's ability to undergo apoptosis= programmed cell death, is the mechanism by which old or damaged cells normally self-destruct.
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Cancer Cell Do Not Grow Faster ThanCancer Cell Do Not Grow Faster Than
Normal CellsNormal Cells
Rather, Their Growth is Just Rather, Their Growth is Just
UncontrolledUncontrolled
Mutations in genes that control cell growth and division are responsible
for cancer.
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Cancer: A Genetic Disease
(cell proliferation and differentiation)
Carcinogens DNA mutations
5ProliferationDifferentiationDeath
Cancer: disruption of cellular equilibrium
What causes Cancer?Cancer is caused by alterations
or mutations in the genetic codeCan be induced in somatic cells
by: Carcinogenic chemicals Radiation Some viruses
Heredity - 5%
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Hanahan and Weinberg, Cell 100: 57, 2000
Apoptosis
Oncogenes
Tumor Suppressor
Inv. and MetsAngiogenesis
Cell cycle
The START Checkpoint
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Mitotic M-cyclinsMitotic M-cdks
S cyclins
/A
Cdc2 (Cell Division Cycle ) = CDK (Cyclin-dependent kinase)9
Checkpoints in Tumor Cells
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In tumor cells, cell cycle checkpoints are often deregulated → 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 complexesin genes encoding proteins that regulate the
abundance of these complexes.
Cancer and Programmed Cell Death
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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.
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•Cancer is a genetic disease.• Mutations in genes result in altered proteins
– During cell division– External agents– Random event
• Most cancers result from mutations in somatic cells.
• Some cancers are caused by mutations in germ line cells.
What is the molecular basis What is the molecular basis of cancer?of cancer?
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1- Standard Dogma• Proto-oncogenes (Ras – melanoma)• Tumor suppressor genes (p53 – various cancers)
2- Modified Dogma• Mutation in a DNA repair gene leads to the
accumulation of unrepaired mutations (xeroderma pigmentosum)
3- Early-Instability Theory• Master genes required for adequate cell
reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome)
Theories of cancer Theories of cancer genesisgenesis
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Chromosomal changes in the genome of cancer cells
TerminalDeletion
http://www.tokyo-med.ac.jp/genet/cai-e.htm
RingChromosome
RobertsonianTranslocation
Deletion Reciprocaltranslocation
IsochromosomesInsertion Inversion
Duplication
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Carcinogenic chemicals
UV Replication Errors
Radiation
Viruses
Rearrangements (translocation, deletions, amplifications)
Point mutations
Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal)
Cancer cell
Normal cell
Damaged DNA
THE CAUSES OF GENOMIC CHANGES IN CANCER
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o Oncogenes o Tumor suppressor geneso DNA repair genes
GENES PLAYING ROLE IN CANCER DEVELOPMENT
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What are the genes responsible for tumorigenic cell growth?What are the genes responsible for tumorigenic cell growth?
Normal
Cancer
Proto-oncogenes Cell growthand
proliferationTumor suppressor genes
+
-
Mutated or “activated”oncogenes Malignant
transformationLoss or mutation of
Tumor suppressor genes
++
ONCOGENEONCOGENESS
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Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.
Oncogenes are genes that, when mutated, actively promote cell proliferation.
Oncogenes are mutated forms of cellular proto-oncogenes.
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proto-oncogene = rasOncogene = mutated rasAlways activatedAlways stimulating proliferation
→→ONCOGENESONCOGENES
The c-ras Gene
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The c-H-ras oncogene was identified by the transfection test (homologue to the Harvey strain of the rat sarcoma virus)
The mutant c-H-ras protein has a mutation that impairs its ability to hydrolyze GTP. This keeps the mutant protein in an active signaling mode and causes it to stimulate cell division.
Mutant versions of c-ras have been found in many types of tumors.
→→ONCOGENESONCOGENES
Normal Ras Protein Signaling
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Mutant Ras Protein is Unregulated
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Class I: Growth Factors
Class II: Receptors for Growth Factors and Hormones
Class III: Intracellular Signal Transducers
Class IV: Nuclear Transcription Factors
Class V: Cell-Cycle Control Proteins
Five types of proteins encoded by proto-Five types of proteins encoded by proto-oncogenes participate in control of cell oncogenes participate in control of cell growth:growth:
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4. NuclearProteins:
TranscriptionFactors
5. Cell GrowthGenes
3. CytoplasmicSignal Transduction
Proteins
1. Secreted Growth Factors
2. Growth Factor Receptors
Functions of Cellular Proto-Oncogenes
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amino acid position
Ras gene 12 59 61 Tumor
c-ras (H, K, N) Gly Ala Gln normal cells
H-ras Gly Ala Leu lung carcinomaVal Ala Gln bladder carcinoma
K-ras Cys Ala Gln lung carcinomaArg Ala Gln lung carcinomaVal Ala Gln colon carcinoma
N-ras Gly Ala Lys neuroblastomaGly Ala Arg lung carcinoma
Murine sarcoma virus
H-ras Arg Thr Gln Harvey strainK-ras Ser Thr Gln Kirsten strain
Amino acid substitutions in Ras family proteins (inactivates GTPase)
Activation mechanisms of proto-oncogenesActivation mechanisms of proto-oncogenes
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proto-oncogene --> oncogene
Viral Oncogenes and Cancer
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Some viral oncogenes produce more protein than their cellular counterpart.
Other viral oncogenes express their proteins at inappropriate times.
Other viral oncogenes express mutant forms of the cellular proteins.
Tumor suppressor genesTumor suppressor genes
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Normal function - inhibit cell proliferation
Tumor suppressor genes are genes that, when mutated, fail to repress cell division.
Absence/inactivation of inhibitor --> cancer
Both gene copies must be defective
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TUMOR SUPPRESSOR GENES
Disorders in which gene is affected
Gene (locus) Function Familial Sporadic
DCC (18q) cell surface unknown colorectal interactions cancer
WT1 (11p) transcription Wilm’s tumor lung cancer
Rb1 (13q) transcription retinoblastoma small-cell lung carcinoma
p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer
BRCA1(17q) transcriptional breast cancer breast/ovarian tumors
BRCA2 (13q) regulator/DNA repair