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Chapter 21 The Genetic (Cell Biology) Basis of Cancer

Chapter 21 The Genetic (Cell Biology) Basis of Cancer. Chapter Outline. Cancer: A Genetic Disease Oncogenes Tumor Suppressor Genes Genetic Pathways to Cancer Tumors in Plants. Cancer: A Genetic Disease.

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Chapter 21 The Genetic (Cell Biology) Basis of Cancer

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  1. Chapter 21The Genetic (Cell Biology) Basis of Cancer © John Wiley & Sons, Inc.

  2. Chapter Outline • Cancer: A Genetic Disease • Oncogenes • Tumor Suppressor Genes • Genetic Pathways to Cancer • Tumors in Plants © John Wiley & Sons, Inc.

  3. Cancer: A Genetic Disease Mutations in genes that control cell growth and division are responsible for cancer. (cell proliferation and differentiation) Carcinogens  DNA mutations © John Wiley & Sons, Inc.

  4. Cancer • Cancers arise when critical genes are mutated, causing unregulated proliferation of cells. • These rapidly dividing cells pile up on top of each other to form a tumor. • When cells detach from the tumor and invade surrounding tissues, the tumor ismalignantand may form secondary tumors at other locations in a process called metastasis. • A tumor whose cells do not invade surrounding tissues is benign.

  5. Tumor – is a condition where there is abnormal cellular growth thus forming a lesion or in most cases, a lump in some part of your body. Benign tumor – grows in confined area Malignant tumor – capable of invading surrounding tissues Cancer – degenerative disease with a cellular condition where there is uncontrolled growing mass of cells capable of invading neighboring tissues and spreading via body fluids to other parts of the body.

  6. Named for site of origin Carcinomas – epithelial cells; cover external & internal body surfaces (90%) Sarcomas – supporting tissue; bone, cartilage, fat, connective tissue, pancreas, Liver. Lymphoma & leukemias – blood & lymphatic tissue (leukemia reserved for cancers that reside in bloodstream not as solid tissue)

  7. Comparison of Normal and Tumor Growth in the Epithelium of the Skin

  8. Comparison of Normal and Tumor Growth in the Epithelium of the Skin Location/distribution

  9. Growth properties of normal and cancerous cells

  10. Hematoxylin (nucleus) and Eosin (cytoplasm) stain

  11. Normal cells vs. Cancer cells independent

  12. Basic Properties of a Cancer Cell In culture, normal cells can be transformed by chemicals or viruses. Different types of cancer cells share a number of similarities: Aberrant chromosome numbers (aneuploidy) High metabolic requirements Unregulated growth Synthesis of unusual cell surface proteins

  13. Stages in the Process of Invasion and Metastasis Basal lamina Invasion Metastasis Matrix Why? How?

  14. Basal lamina Loss of cell surface proteins involve in cell-cell adhesion E-cadherin Increased Motility signaling molecules, chemoattractants, protease activator (plasminogen plasmin)

  15. Some cells are more capable than others 99%

  16. Some preferential sites blood flow patterns: capillaries (5-10 um of diametervs 20 x 25 um) “seed and soil” Surrounding environment

  17. Cancers © John Wiley & Sons, Inc.

  18. Cell Cycle Checkpoints • Transitions between different phases of the cell cycle (G1, S, G2, and M) are regulated at checkpoints. • A checkpoint is a mechanism that halts progression through the cycle until a critical process is completed. © John Wiley & Sons, Inc.

  19. Cyclins and CDKs • Important checkpoint proteins are the cyclins and the cyclin-dependent kinases (CDKs);complexes formed between cyclins and CDKs cause the cell cycle to advance. • The CDKs phosphorylate target proteins but are inactive unless they are associated with a cyclin protein. • Cell cycling requires the alternate formation and degradation of cyclin/CDK complexes. © John Wiley & Sons, Inc.

  20. The START Checkpoint © John Wiley & Sons, Inc.

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

  22. Checkpoints in Tumor Cells • In tumor cells, cell cycle checkpoints are often deregulated due to genetic defects in the machinery that alternately raises and 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. © John Wiley & Sons, Inc.

  23. 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. © John Wiley & Sons, Inc.

  24. Major Steps in Apoptosis ‘bubble” Necrosis= injury Apoptosis= program for cell death

  25. Induction of Apoptosis by Cell Death Signals or by Withdrawal of Survival Factors Killer lymphocytes Autoproteolysis ATP proteolysis IGFR=insulin-like growth factor receptor INSR= insulin receptor

  26. Evidence of a Genetic Basis for Cancer • The cancerous state is clonally inherited. • Some types of viruses can induce the formation of tumors in experimental animals. • Cancer can be induced by mutagens. • Certain types of white blood cell cancers are associated with particular chromosomal abnormalities. © John Wiley & Sons, Inc.

  27. Cancer and Genes • Oncogenes are genes that, when mutated, actively promote cell proliferation. • Tumor suppressor genesare genes that, when mutated, fail to repress cell division. © John Wiley & Sons, Inc.

  28. Oncogenes … the overexpression of certain genes …the abnormal activity of certain genes …their mutant protein products. © John Wiley & Sons, Inc.

  29. Tumor-Inducing Retroviruses and Viral Oncogenes • Retroviruses have an RNA genome. • The Rous sarcoma virus, the first tumor-inducing virus, contains four genes • gag encodes the capsid protein of the virus • pol encodes the reverse transcriptase • env encodes a viral envelope protein • v-src encodes a protein kinase that inserts into the plasma membranes of infected cells. The v-src gene is an oncogene that is responsible for the virus’s ability to induce abnormal cell growth. © John Wiley & Sons, Inc.

  30. Proteins Encoded by Viral Oncogenes • Growth factors similar to those encoded by cellular genes • Proteins similar to growth-factor and hormone receptors • Tyrosine kinases that do not span the plasma membrane • Transcription factors homologous to cellular proteins • Any protein © John Wiley & Sons, Inc.

  31. Human? © John Wiley & Sons, Inc.

  32. Proto-Oncogenes • The proteins encoded by viral oncogenes are similar to cellular proteins with important regulatory functions. • These cellular homologues are called proto-oncogenes or normal cellular genes. • The normal c-oncogeneshave introns; the viral v-oncogenes often lack introns. • From c-onco to v-onco….. Replication-defective viruses © John Wiley & Sons, Inc.

  33. Normal gene Cell-oncogene (c-onc) Replication-defective virus

  34. The Transfection Test to Identify Mutant Cellular Oncogenes © John Wiley & Sons, Inc.

  35. 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. © John Wiley & Sons, Inc.

  36. The c-ras Gene • The c-H-rasoncogene 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. © John Wiley & Sons, Inc.

  37. Normal Ras Protein Signaling © John Wiley & Sons, Inc.

  38. Mutant Ras Protein (V12 or G12V) is Unregulated © John Wiley & Sons, Inc.

  39. Mutations in c-ras are Dominant • A single mutant c-ras allele is dominant in its ability to bring out the cancerous state. • Mutations in c-ras and other oncogenes are dominant activatorsor uncontrolled cell growth. • Most dominant activating mutations in cellular oncogenes occur spontaneously in somatic cells, not in the germline. © John Wiley & Sons, Inc.

  40. Cancer is the Result of Several Mutations • A single mutation usually does not result in cancer. • Usually several genes that regulate cell growth are mutated before a cancerous state results. © John Wiley & Sons, Inc.

  41. Chromosome Rearrangements: The Philadelphia Chromosome • The Philadelphia chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 with breakpoints in the c-abl gene on chromosome 9 and the c-bcr gene on chromosome 22. • The fusion gene created by this rearrangement encodes a tyrosine kinase that promotes cancer in white blood cells. © John Wiley & Sons, Inc.

  42. The Philadelphia Chromosome © John Wiley & Sons, Inc.

  43. Chromosomal Rearrangements:Burkitt’s Lymphoma • Burkitt’s lymphoma is associated with reciprocal translocations involving chromosome 8 and a chromosome carrying an immunoglobulin gene (2, 14, or 22). • The translocations juxtapose c-myc to the genes for the immunoglobulin genes, causing overexpression of c-myc in B cells. • The c-myc gene encodes a transcription factor that activates genes for cell division. © John Wiley & Sons, Inc.

  44. A Reciprocal Translocation Involved in Burkitt’s Lymphoma 8p21.1 © John Wiley & Sons, Inc.

  45. Tumor Suppressor Genes Many cancers involve the inactivation of genes whose products play important roles in regulating the cell cycle. C-ras and c-myc……genes required for regulation cell cycle. -increase activity and/or concentration-----oncogene----may form tumors. -decrease activity and/or concentration----anti-oncogene----not tumor formation © John Wiley & Sons, Inc.

  46. Knudson’s Two-Hit Hypothesis • When tumor suppressor genes are mutated, a predisposition to develop cancer often follows a dominant pattern of inheritance. • The mutation is usually a loss-of-function mutation in the tumor suppressor gene. • Cancer develops only if a second mutation in somatic cells knocks out the function of the wild-type allele. © John Wiley & Sons, Inc.

  47. © John Wiley & Sons, Inc.

  48. Verification of the Two-Hit Hypothesis for Retinoblastoma • Several cases of retinoblastoma are associated with a small deletion in chromosome 13q. Mapping refined the RB locus to 13q14.2. • Positional cloning was used to isolate a candidate RB gene that encodes a protein that interact with transcription factors that regulate the cell cycle. • In retinoblastoma cells, both copies of this gene were inactivated. • In cell culture, expression of a wild-type RB allele could revert the phenotype of cancer cells. © John Wiley & Sons, Inc.

  49. © John Wiley & Sons, Inc.

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