Dr MOHAMED FAKHRY 2015 1 MOLECULAR BASIS OF CANCER.

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.

2


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.


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


Mitotic M-cyclinsMitotic M-cdks

S cyclins

/A

Cdc2 (Cell Division Cycle ) = CDK (Cyclin-dependent kinase)9

Checkpoints in Tumor Cells


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


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.


•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?


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


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


o Oncogenes o Tumor suppressor geneso DNA repair genes

GENES PLAYING ROLE IN CANCER DEVELOPMENT


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


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.


proto-oncogene = rasOncogene = mutated rasAlways activatedAlways stimulating proliferation

→→ONCOGENESONCOGENES

The c-ras Gene


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


Mutant Ras Protein is Unregulated



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:


4. NuclearProteins:

TranscriptionFactors

5. Cell GrowthGenes

3. CytoplasmicSignal Transduction

Proteins

1. Secreted Growth Factors

2. Growth Factor Receptors

Functions of Cellular Proto-Oncogenes


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


proto-oncogene --> oncogene

Viral Oncogenes and Cancer


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


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

Dr MOHAMED FAKHRY 2015 1 MOLECULAR BASIS OF CANCER.

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