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MOLECULAR BASIS OF CANCER

MOLECULAR BASIS OF CANCER. Cellular Basis of Cancer. Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just Uncontrolled. 1 fertilized egg. 50x10 12. Proliferation. Death. Differentiation. 10 16 cell divisions/lifetime. Renewing. Cellular equilibrium.

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MOLECULAR BASIS OF CANCER

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  1. MOLECULAR BASIS OF CANCER

  2. Cellular Basis of Cancer

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

  4. 1 fertilized egg 50x1012 Proliferation Death Differentiation 1016 cell divisions/lifetime

  5. Renewing Cellular equilibrium Proliferation Death Differentiation Transit Proliferating Exiting

  6. Cancer: disruption of cellular equilibrium Proliferation Differentiation Death

  7. Stem cells as the target of carcinogens Grade 3 or 4 malignancy Grade 2 malignancy Benign tumor Post mitotic Stem cell Normal senescent differentiated cell Differentiated

  8. 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%

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

  10. What is the molecular basis of cancer? • 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 germline cells

  11. THE CAUSES OF GENOMIC CHANGES IN CANCER UV Replication Errors Carcinogenic chemicals Radiation Normal cell Viruses Damaged DNA Rearrangements (translocation, deletions, amplifications) Point mutations Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal) Cancer cell

  12. GENES PLAYING ROLE IN CANCER DEVELOPMENT • Oncogenes • Tumor suppressor genes • DNA repair genes

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

  14. ONCOGENES • Oncogenes are mutated forms of cellular proto-oncogenes. • Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.

  15. Five types of proteins encoded by proto-oncogenes participate in control of cell growth: 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

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

  17. Oncogenes proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation

  18. Activation mechanisms of proto-oncogenes proto-oncogene --> oncogene

  19. CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc1 Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2 leukemia 1c-myc is translocated to the IgG locus, which results in its activated expression 2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

  20. GENE AMPLIFICATION Oncogene Amplification Source of tumor c-myc ~20-fold leukemia and lung carcinoma c-abl ~5-fold chronic myoloid leukemia

  21. Oncogenes are usually dominant • (gain of function) • cellular proto-oncogenes that have been mutated (and “activated”) • cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”) • virus-specific genes that behave like cellular proto-oncogenes that have been mutated to oncogenes (i.e., “activated”)

  22. The result: • Overproduction of growth factors • Flooding of the cell with replication signals • Uncontrolled stimulation in the intermediary pathways • Cell growth by elevated levels of transcription factors

  23. Tumor suppressor genes • Normal function - inhibit cell proliferation • Absence/inactivation of inhibitor --> cancer • Both gene copies must be defective

  24. TUMOR SUPPRESSOR GENES Disorders in which gene is affected Gene (locus) Function Familial Sporadic 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

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