1. Dr MOHAMED FAKHRY 2015 1 MOLECULAR BASIS OF CANCER

2. 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 from 1) uncontrolled cell growth or 2) 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

3. Dr MOHAMED FAKHRY 2015 3 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just Uncontrolled

4. Mutations in genes that control cell growth and division are responsible for cancer. Dr MOHAMED FAKHRY 2015 4 Cancer: A Genetic Disease (cell proliferation and differentiation) Carcinogens  DNA mutations

5. 5 Proliferation DifferentiationDeath Cancer: disruption of cellular equilibrium

6. What causes Cancer? Cancer is caused by alterations or mutations in the genetic code Can be induced in somatic cells by: Carcinogenic chemicals Radiation Some viruses Heredity - 5% Dr MOHAMED FAKHRY 2015 6

7. 7 Hanahan and Weinberg, Cell 100: 57, 2000 Apoptosis Oncogenes Tumor Suppressor Inv. and Mets Angiogenesis Cell cycle

8. The START Checkpoint Dr MOHAMED FAKHRY 2015 8

9. Mitotic M-cyclins Mitotic M-cdks S cyclins /A Cdc2 (Cell Division Cycle ) = CDK (Cyclin-dependent kinase) 9

10. Checkpoints in Tumor Cells Dr MOHAMED FAKHRY 2015 10 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 complexes in genes encoding proteins that regulate the abundance of these complexes.

11. Cancer and Programmed Cell Death Dr MOHAMED FAKHRY 2015 11 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.

12. Dr MOHAMED FAKHRY 2015 12 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 of cancer?

13. Dr MOHAMED FAKHRY 2015 13 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 genesis

14. Dr MOHAMED FAKHRY 2015 14 Chromosomal changes in the genome of cancer cells Terminal Deletion http://www.tokyo-med.ac.jp/genet/cai-e.htm Ring Chromosome Robertsonian Translocation Deletion Reciprocal translocation IsochromosomesInsertionInversion Duplication

15. 15 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

16. Dr MOHAMED FAKHRY 2015 16 o Oncogenes o Tumor suppressor genes o DNA repair genes GENES PLAYING ROLE IN CANCER DEVELOPMENT

17. Dr MOHAMED FAKHRY 2015 17 What are the genes responsible for tumorigenic cell growth? Normal Cancer Proto-oncogenes Cell growth and proliferation Tumor suppressor genes + - Mutated or “activated” oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes ++

18. ONCOGENES Dr MOHAMED FAKHRY 2015 18 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.

19. Dr MOHAMED FAKHRY 2015 19 proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation → ONCOGENES

20. The c-ras Gene Dr MOHAMED FAKHRY 2015 20 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. → ONCOGENES

21. Normal Ras Protein Signaling Dr MOHAMED FAKHRY 2015 21

22. Mutant Ras Protein is Unregulated Dr MOHAMED FAKHRY 2015 22

23. Dr MOHAMED FAKHRY 2015 23 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-oncogenes participate in control of cell growth:

24. Dr MOHAMED FAKHRY 2015 24 4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes 3. Cytoplasmic Signal Transduction Proteins 1. Secreted Growth Factors 2. Growth Factor Receptors Functions of Cellular Proto-Oncogenes

25. Dr MOHAMED FAKHRY 2015 25 amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N)GlyAlaGlnnormal cells H-rasGlyAlaLeulung carcinoma ValAlaGlnbladder carcinoma K-rasCysAlaGlnlung carcinoma ArgAlaGlnlung carcinoma ValAlaGlncolon carcinoma N-rasGlyAlaLysneuroblastoma GlyAlaArglung carcinoma Murine sarcoma virus H-rasArgThrGlnHarvey strain K-rasSerThrGlnKirsten strain Amino acid substitutions in Ras family proteins (inactivates GTPase)

26. Activation mechanisms of proto-oncogenes Dr MOHAMED FAKHRY 2015 26 proto-oncogene --> oncogene

27. Viral Oncogenes and Cancer Dr MOHAMED FAKHRY 2015 27 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.

28. Tumor suppressor genes Dr MOHAMED FAKHRY 2015 28 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

29. 29 TUMOR SUPPRESSOR GENES Disorders in which gene is affected Gene (locus) Function Familial Sporadic DCC (18q) cell surface unknowncolorectal interactions cancer WT1 (11p) transcription Wilm’s tumorlung cancer Rb1 (13q) transcription retinoblastoma small-cell lung carcinoma p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer BRCA1(17q) transcriptionalbreast cancerbreast/ovarian tumors BRCA2 (13q) regulator/DNA repair