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THE MOLECULAR BASIS OF CANCER

THE MOLECULAR BASIS OF CANCER

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THE MOLECULAR BASIS OF CANCER

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  1. THE MOLECULAR BASIS OF CANCER

  2. THE MOLECULAR BASIS OF CANCER • Nonlethal genetic damage lies at the heart of carcinogenesis. • Number of hypothesis proposed and rejected grow more rapidly than the growth of highly malignant tumors • Knowledge on oncogenic pathway is doubling every 3 years

  3. THE MOLECULAR BASIS OF CANCER • The genetic hypothesisof cancer implies that a tumor mass results from the clonal expansion of a single progenitor cell that has incurred the genetic damage. • Clonality of tumors.

  4. THE MOLECULAR BASIS OF CANCER • Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.

  5. Primary or environment (75%) Alterations to the human genome First hit Second hit Cancer genome Normal genome TIME Carcinogenesis is a multistep event with somatic mutations

  6. Normal tissue (epithelium) dysplasia sequence in cervical carcinoma Dysplastic epithelium CIN (I-IV) Intraepithelial lesion CIS Carcinoma in situ (no penetration of BM) Invasive Carcinoma (BM destroyed) Loss of polarity/maturation pattern Increased number of mitotic figure Variation of cell size /shape (pleomorfism) Large nuclei/cytoplasmic ratio Hyperchromatic nuclei Primitivity of nuclear chromatin (altered differentiation) Rarely curable Curable Curable

  7. Dysplasia neoplasia sequence in colonic carcinoma

  8. Dysplasia neoplasia sequence in colonic carcinoma

  9. THE MOLECULAR BASIS OF CANCER • Tumor progressionresults from the accumulation of genetic lesions involving: 1- growth-regulatory genes 2- genes that regulate angiogenesis 3- genes that regulate invasion and metastases • Cancer cells also must bypass the normal process of DNA repair and aging that limits cell division

  10. THE MOLECULAR BASIS OF CANCERGrowth-regulatory genes • Three classes of normal regulatory genes • growth-promoting protooncogenes • growth-inhibiting cancer suppressor genes (antioncogenes) • genes that regulate programmed cell death (apoptosis) These are the principal targets of genetic damage.

  11. THE MOLECULAR BASIS OF CANCER • A fourth category of genes: genes regulate repair of damaged DNA

  12. THE MOLECULAR BASIS OF CANCER • Six acquired capabilities of cancer cells: 1. Self-sufficiency in growth signals. 2. Insensitivity to growth-inhibitory signals. 3. Evasion of apoptosis. 4. Limitless replicative potential (e.g. over- coming cellular senescence). 5. Sustained angiogenesis. 6. Ability to invade and metastasize. • When genes that normally sense and repair DNA damage are lost (enabler genes), the resultant genomic instability favors mutations in genes that regulate the six acquired capabilities of cancer cells.

  13. THE MOLECULAR BASIS OF CANCER SELF SUFFICIENCY IN GROWTH SIGNALS • Genes that promote autonomous cell growth in cancer cells are called oncogenes. • Derived by mutations in protooncogenes. • Oncoproteins control the sequence of events that characterize normal cell proliferation.

  14. THE MOLECULAR BASIS OF CANCER • Oncogenes and oncoproteins • Growth factors • Growth factors receptors • Intracellular signaling transducing proteins • Nuclear transcription factors • Entry of the cell in cell cycle

  15. Events that characterize normal cell proliferation. • The binding of a growth factor to its specific receptor in the cell membrane. • Transient and limit activation of the growth factor receptor, which in turn activates several signal-transducing proteins on the inner leaflet of the plasma membrane. • Transmission of the transduced signal across the cytosol to the nucleus via second messengers. • Induction and activation of nuclear regulatory factors that initiate DNA transcription. • Entry and progression of the cell into the cell cycle.

  16. GROWTH FACTORS (GF) • Paracrine and autocrine • Cancer cells acquire self-sufficiency in growth signals by acquiring the ability to synthesize GF • Examples: PDGF in glioblastoma • TGF-alpha in sarcomas • Mutation of GF genes or the products of other genes e.g. RAS cause • Overexpression of GF genes GF

  17. GROWTH FACTOR RECEPTORS Mutation and overexpression of GROWTH FACTOR RECEPTORS found in many tumors e.g. EGF receptor family: ERBB1, 80% of SCC of Lung ERBB2 (HER2),25-30% of breast CA, adenocarcinoma of lung, ovary and salivary glands

  18. SIGNAL-TRANSDUCING PROTEINS

  19. Principle of signalling Common mechanism e.g. RASandABL genes

  20. Signaling completed successfully - transcription proceeds

  21. RAS gene RAS-RAFcascade RAS genemutation found in 30% of all human tumorse.g. carcinomas of colon, pancreas & thyroid GTPase activating protein (GAPs) NF-1 mutation in familial neurofibromatosis type 1

  22. MAP kinase • Mitogen-activated protein kinase (mitogens are hormones that cause mitosis) • Activated by a kinase cascade: MAP kinase is phosphorylated and activated by MEK (MAP kinase) MEK (MAP kinase) is phosphorylated and activated by Raf Raf is activated by Ras

  23. SIGNAL-TRANSDUCING PROTEINS • ABL gene • Found in 90% of chronic myeloid leukemia • BCR- ABL hybrid has potent tyrosine kinase activity that activates cell growth by several pathways including • RAS-RAFcascade • Normal ABL protein localizes in nucleus to promote apoptosis • Drug STI 571 act in both ways

  24. NUCLEAR TRANSCRIPTION FACTORS MYC gene bind to DNA and activate transcription of several growth related genes e.g. CDKs C-MYC gene is amplified in CA breast, colon lungs N-MYC gene is amplified in neuroblastomas L-MYC gene is amplified in small cell CA

  25. NUCLEAR TRANSCRIPTION FACTORS • MYC gene is dysregulated in 90% of Burkitt lymphoma

  26. NUCLEAR TRANSCRIPTION FACTORS N-MYC gene is amplified in neuroblastomas

  27. CYCLINS AND CYCLIN-DEPENDENT KINASES

  28. Cell cycle: A

  29. Cell cycle: checkpoints CDK6/cyclinD/CDK4 cyclin2/CDK2 complex Rb Rbpp 1 Release of E2F TF 1a Transcription begins 2a Completion of S 2 Spindle checkpoint p53 protein binds p21 (block inhibition)

  30. CYCLINS AND CYCLIN-DEPENDENT KINASES • Cyclin D gene is overexpressed in cancers of breast, esophagus, liver and some types of lymphoma • Amplification of CDK4 gene occur in melanoma, sarcoma and glioblastoma • At least one of the four key regulators of cell cycleis mutated in most human cancers(INK4a, cyclin D, CDK4, RB)

  31. INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS Cancer suppressor genes The products of tumor suppressor genes apply brakes to cell proliferation whereas oncogenes encode proteins that promote cell growth • Disruption of cancer suppressor genes renders cells refractory to growth inhibition. • e.g. Retinoblastoma (RBgene), TP53, TGF-, APC • Two hit hypothesis.

  32. INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS Cancer suppressor genes Two hit hypothesis. • Heterozygous. • Homozygous. • Lose of heterozygosity. • Recessive cancer genes

  33. Cancer suppressor genes • Prevent cell proliferation by two complementary mechanisms: 1- Cause dividing cells to go into G0 2- Cell enter a postmitotic, differentiated pool and lose its replicative potential.

  34. Cancer suppressor genes

  35. Cancer suppressor genes • Retinoblastoma gene ( RB gene): • Two mutations (hits) are required to produce retinoblastoma • These involve the RB gene, located on chromosome 13q14. • The RB gene product is a DNA-blinding protein that is expressed in every cell type examined. • Found in other neoplasms e.g. breast cancer, small cell cancer of the lung, and bladder cancer.

  36. INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS RB gene • Sporadic cases: 60% • -2 hits are required. • Familial cases: 40% • -one hit is rerquired. • -Patients withfamilial retinoblastoma also are at greatly increased risk of developing osteosarcomas, breast carcinoma, small cell carcinoma of lung, some soft tissue sarcomas and some brain tumor.

  37. INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS RB GENE AND CELL CYCLE • RB serves as a brake in the advancement of cells from G1 to the S phase of the cell type. • Quiescent cells (in G0 to G1) contain the active hypophosphorlyated form of RB. • RB prevents cell replication by binding and possibly sequestering, the E2F family of transcription factors.

  38. RB GENE AND CELL CYCLE RB a brake

  39. TO CYCLE OR NOT TO CYCLE: A CRITICAL DECISION IN CANCER