Multistep Theory of Carcinogenesis PDF

Multistep Theory of Carcinogenesis Prof Thidar Aung Learning Objectives Cellular and molecular events in carcinogenesis Students will be able to 1. Describe the multistep theory of neoplasia with diagram. 2. Describe the genetic abnormalities in carcinogenesis. 3. State the hallmarks of cancer. Mani...

Multistep Theory of Carcinogenesis Prof Thidar Aung Learning Objectives Cellular and molecular events in carcinogenesis Students will be able to 1. Describe the multistep theory of neoplasia with diagram. 2. Describe the genetic abnormalities in carcinogenesis. 3. State the hallmarks of cancer. Manipal University College Malaysia (MUCM) 2 Carcinogenesis Carcinogenesis is a process that results in the transformation of normal cells to neoplastic cells by causing permanent genetic alterations. Carcinogen / carcinogenic agents A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. Three classes of carcinogenic agents can be identified: (1) chemicals (2) radiant energy and (3) microbial agents Manipal University College Malaysia (MUCM) 3 The multistep carcinogenesis hypothesis More than one carcinogen is necessary for the complete neoplastic transformation of a cell, and there is good evidence that the process occurs in several discrete steps. Evidence for a multistep theory is derived from observations on the experimental induction of tumours in laboratory animals and the sequential genetic alterations in the development of human tumours Steps in experimental carcinogenesis two major steps – initiation and promotion – in the transformation of cells A further step – Progression – resulting in the malignant phenotype Manipal University College Malaysia (MUCM) 4 The conventional multistage evolution of tumour cells Multistep process May require initiating and promoting agents Growth persists in the absence of the causative agents Genetic alterations of oncogenes and tumour suppressor genes Manipal University College Malaysia (MUCM) 5 Once established, neoplastic behaviour does not require the continued presence of the carcinogen. It is a ‘hit-and run’ situation Evidence of the specific causative agent(s) is not usually found in the eventual tumours. Exceptions: some suspected carcinogenic viruses genetic material of which persists in the resulting tumours some insoluble substances, such as asbestos Manipal University College Malaysia (MUCM) 6 Two models for heterogeneity & differences in tumour-regenerative capacity: 1. Clonal evolution model 2. Cancer stem cell model 1. Clonal evolution model - Mutant tumour cells with a growth advantage are selected and expanded. - Neoplasms arise from single cells that have become transformed by cumulative mutational events. - All cells in the dominant population have a similar potential for initiating tumour growth. - Because of this, neoplasms are said to be clonal proliferations. - The probability of neoplastic transformation increases with the number of cell divisions experienced by a cell.(the incidence of cancer increases with age) Manipal University College Malaysia (MUCM) 7 1. CLONAL EVOLUTION MODEL Mutation 1 Mutation 2 …Mutation n malignant tumour Selective growth advantage of clone with mutation 1 Increased resistance to apoptosis with mutation 2 Continuing evolution by natural selection Each successive mutation gives the cell a growth advantage 8 2. Cancer stem cell model ₋ Tumours composed of cells that can initiate tumours (tumour initiating cells or cancer stem cells [CSCs]) and cells that arise from CSCs but cannot initiate tumours. ₋ CSCs have the ability to self-renew and generate diverse tumour cells. ₋ Frequency of CSC in a tumour is highly variable (often low). ₋ CSC have been identified prospectively e.g. Breast Cancer; Colon Cancer; Leukemia; Prostate Cancer; Melanoma; Pancreatic Cancer & Some Malignant Brain Tumours ₋ CSCs may have different sensitivities to radiation or chemotherapy. Therefore, significant clinical implications. https://www.youtube.com/watch?v=50wt39Cpklk Manipal University College Malaysia (MUCM) 9 Cancer Stem Cell Hypothesis Essential for the initiation and long term maintenance of the tumour Responsible for the expansion of the tumour – incapable of long term maintenance of the tumour. Perhaps post-mitotic in some cases, in others, further proliferation is possible. Incapable of maintaining the tumour. Much of the tumour cell population Adapted from: Figure 11.16b The Biology of Cancer (© Garland Science 2007) Multistep Development of Colon Cancer Vogelstein’s theory of colonic carcinogenesis Different genetic changes are associated with progression of adenoma of colon (benign neoplasm) to carcinoma of the colon More than one somatic mutation is generally needed to produce a fullfledged cancer cell About 6-7 DNA changes must occur for a cell to become fully cancerous Typically occur over several decades Usually includes at least one active oncogene and mutation or loss of several tumour-suppressor genes Manipal University College Malaysia (MUCM) 11 Multistep Development of Colon Cancer [APC: adenomatosis polyposis coli] Manipal University College Malaysia (MUCM) [DCC: deleted in colon cancer] 12 Genetic abnormalities in carcinogenesis MUTATIONS IN FOUR CLASSES OF GENES CAN CAUSE CANCER 1. 2. Growth-promoting Proto-oncogenes Normal activity: to promote cell proliferation Mutant forms : oncogenes Gain-of-function mutation create forms excessively active A single mutant allele may affect cell phenotype Growth-inhibiting Tumour suppressor genes Normal activity: to inhibit cell proliferation or promote apoptosis Loss of function mutation Both alleles often inactivated, but haploinsufficiency for some Manipal University College Malaysia (MUCM) 3. Apoptosis regulating genes Mutation result in less cell death, enhanced survival. E.g., gain-of-function mutations in genes whose products suppress apoptosis loss-of-function mutations in genes whose products promote cell death. 4. DNA Repair Genes Loss-of-function mutations impair ability of the cell to recognize and repair nonlethal genetic damage in other genes. affected cells acquire mutations at an accelerated rate (mutator phenotype) 13 Hallmarks of Cancer – Essential alterations in cell physiology Six biological capabilities acquired during the multistep development of human tumours. From Hanahan D, Weinberg RA, Cell 2011;144:646 facilitate acquisition of both core & emerging hallmarks 16 FURTHER READING Robbins Cotran Pathologic Basis of Disease 10th Ed, Chapter 7, Neoplasia Underwoods Pathology A Clinical Approach 7th Ed, Chapter 10, Carcinogenesis and Neoplasia Manipal University College Malaysia (MUCM) 17