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Cancer Doesn’t Happen Overnight

Cancer Doesn’t Happen Overnight. The Multi-Step Origin of Cancer. Cancer Occurrence With Age. The curve is an exponential rather than additive curve Multiple events must occur before the threshold is met.

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Cancer Doesn’t Happen Overnight

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  1. Cancer Doesn’t Happen Overnight The Multi-Step Origin of Cancer

  2. Cancer Occurrence With Age • The curve is an exponential rather than additive curve • Multiple events must occur before the threshold is met. • Once a critical number of events have occurred the likelihood of cancer increases rapidly • There is no “upper” boundary on the curve

  3. Most Carcinogens are Mutagens The Ames test for mutagenicity.The test uses a strain of Salmonella bacteria that require histidine in the medium because of a defect in a gene necessary for histidine synthesis. Mutagens can cause a further change in this gene that reverses the defect, creating revertant bacteria that do not require histidine. To increase the sensitivity of the test, the bacteria also have a defect in their DNA repair machinery that makes them especially susceptible to agents that damage DNA. A majority of compounds that are mutagenic in tests such as this are also carcinogenic and vice versa

  4. Carcinogens Listed in the Eleventh Report- NIH Toxicology Program Part A. Known to be Human Carcinogens. (abbreviated list) Name or synonym Page No. Aflatoxins 8 Alcoholic Beverage Consumption 10 Analgesic Mixtures Containing Phenacetin 212 Arsenic Compounds, Inorganic 18 Asbestos 21 Benzene 26 Coal Tars (See Coal Tars and Coal Tar Pitches) 68 Coke Oven Emissions 71 Diethylstilbestrol 98 Dyes Metabolized to Benzidine (See Benzidine and Dyes Metabolized to Benzidine) 29 Environmental Tobacco Smoke (See Tobacco Related Exposures) 251 Estrogens, Steroidal 115 Ethylene Oxide 118 Hepatitis B Virus 131 Hepatitis C Virus 133 Human Papillomas Viruses: Some Genital-Mucosal Types 142 Radon (See Ionizing Radiation) 152 Smokeless Tobacco (See Tobacco Related Exposures) 253 Solar Radiation (See Ultraviolet Radiation Related Exposures) 266 Sunlamps or Sunbeds, Exposure to (See Ultraviolet Radiation Related Exposures) 266 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); “Dioxin” 241 Tobacco Smoking (See Tobacco Related Exposures) 255 Vinyl Chloride 272 Ultraviolet Radiation, Broad Spectrum UV Radiation (See Ultraviolet Radiation Related Exposures) 266 X-Radiation and Gamma Radiation (See Ionizing Radiation) 147 Bold entries indicate new or changed listing in The Report on Carcinogens, Eleventh Edition. Red entries- exposure is common and preventable

  5. Carcinogenesis is Accelerated by Tumor Promoters* *Carcinogens are mutagens; promoters are mitogenic (stimulate cell division).

  6. Steps Toward Cancer • Exposure to carcinogens (mutagens) • Appearance of cells with mutant proto-oncogenes or tumor suppressor genes . These steps are common to the appearance of most cancers. However in some cases exposure to carcinogens is not necessary • Exposure to tumor promoters (mitogens) alone can stimulate cell division and result in higher incidence of replication errors that uncover pre-existing tumor suppressor mutatons

  7. Estrogen as a Tumor Promoter Breast ~ number of menstrual cycles without pregnancy

  8. Tumor Suppressors Like p53 guard the genome • Normal cells have very little p53 • Mice can survive with no p53 gene at all • These mice usually die of cancer at about 3 months. • DNA damage stabilizes p53 • P53 induces p21 • P21 halts the cell cycle • If DNA is not repaired during pause p53 causes apoptosis

  9. Aquired mutations in these tumor suppressor genes can result in sporadic cancer

  10. Proposed steps toward colon cancer Ademotous polyps Colon cancer APC = Tumor suppressor gene often inherited as recessive mutation p53 = Tumor suppressor – prevents replication of damaged DNA K- Ras = Oncogene acts in growth signaling pathway Smad 4 = tumor suppressor slows growth & promotes differentiation

  11. Loss of Checkpoint Control Results in Genetic Instability (A) The karyotype of a typical cancer shows many gross abnormalities in chromosome number and structure. Considerable variation can also exist from cell to cell. (B) The karyotype of a tumor that has a stable chromosome complement with few chromosomal anomalies. Its defects are mostly invisible, having been created by defects in DNA mismatch repair.

  12. Consequences of Genetic Instability • Most cells lose critical genes and die. • Some cells proliferate but are not fit enough to form tumors and eventually die. • Some cells have just the right set of genes to out compete normal cells and other unstable cells and become the progenitors of a carcinoma.

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