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16 Cards in this Set
- Front
- Back
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Main forms of cancers |
Sarcoma = Mesenchymal Carcinoma = Epithelial tissue
Hematopoietic & lymphoid = Leukemia and Lymphoma |
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Cells in the body are programmed to: |
develop, grow, differentiate (into mature cells) and also diein response to a complex system of biochemical signals |
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What is cancer ? Cancer results from the emergence of a clone of cells: |
Freed of programmed constraints (Disruption of orderly and regulated cycle of cell replication and division) That are capable of inappropriate proliferation (Cancer cells duplicate and divide more frequently than neighbouring cells) |
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6 Hallmarks of cancer + 2 new hallmarks |
Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis (spread to other organsand tissues) Limitless replicative potential Sustained angiogenesis (devp of new bloodvessles ) Evading apoptosis (cell death) Reprogramming cellular energy metabolismEvasion of immune destruction |
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Evolution of cancer: Overcoming the defences Given typical mutation rates of 10-7 per gene per cell generation, the probability of any cell sequentially acquiring six specific mutations is |
X10^-36 ....very small chance! Only way is if mutations early in process greatly increase the probability of later mutations |
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Overcoming the defences: Two mechanisms Can do this in either of two ways: |
Mutation(s) can enhance cell proliferation •If mutant cell can generate 1000 mutant daughter cells •Chance that one mutant cell can acquire next mutation is increased 1000-fold |
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Overcoming the defences: Two mechanisms Combination of two mechanisms: |
Mutation(s) can enhance cell proliferation Mutation(s) can increase general mutation rate by destabilizing the genome •All cancer cells show one of two types of genomic instability: •Chromosomal instability |
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Cancer is a genetic disease |
Cancer is a consequence of genetic damage whose cumulative effect results in unrestrained cell growth, tissue invasion, and metastasis. |
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Genes involved. Two distinct categories: |
Proto-oncogenes Tumour suppressor genes |
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Proto-Oncogenes |
Are components of signaling pathways that regulate (drive) cell proliferation and differentiation |
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Proto-Oncogenes: Five broad categories (dependent on function) |
Growth factors Cell surface receptor proteins Cytoplasmic signal transducer proteins Nuclear proteins (transcription factors) Components of the network that govern progress through cell cycle (Cyclins, CDKs, telomerase, etc) Anti-apoptotic proteins |
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How is a proto-oncogene made oncogenic ? (1) |
1. Point mutation Hyperactive protein (Normal amounts) Example: RAS (Bladder cancer) |
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How is a proto-oncogene made oncogenic ? (2) |
2. Amplification Normal protein (Greatly overproduced) Example: N-Myc (Neuroblastoma) |
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How is a proto-oncogene made oncogenic ? (3.1) |
3. Chromosome Translocation 3.1 Up-regulation of expression (Normal protein (Overproduced) Example 1: Burkitt lymphoma= cMYC at 8q24 80% have t(8;14) IgH 15% t(8;22) IgL 5% t(2;8) IgK) Example 2: Follicular B-cell lymphoma= Translocation t(14;18) BCL2 located at 18q21 Mitochondrial anti-apoptotic protein > B -cells Placed under promotor and enhancer of IgH Inappropriate, prolonged expression •Massive expansion of B -cells •Apoptosis inhibited |
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How is a proto-oncogene made oncogenic ? (3.2) |
3. Chromosome Translocation 3.2 Rearrangement of gene Fusion protein (Hyperactive) Common in hematologic tumours & sarcomas – rare in carcinomas Example CML - t(9;22) |
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When a proto-oncogene becomes oncogenic... |
End result is a gain of function Inappropriate “activation” of the protein(s) and its associated pathway(s) Mutations are somatic - Four exceptions MET – Hereditary papillary renal carcinoma RET – Multiple endocrine neoplasia KIT – Gastrointestinal stromal tumour syndrome CDK4 – Malignant melanoma In which germ-line mutations give rise toinherited cancer syndromes |
