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Carcinogenesis Tee L. Guidotti Dept. of Environmental and Occupational Health GWUMC Characteristics of Toxicological Mechanisms Carcinog. Genome Target ? No ThresThreshold hold Outcome Stereotyp Response Stochastic Latency Long Immune Immune Recognition Stereotyp Nonstoch. Short Toxicity Receptor Threshold, dose-dep. Multiple Dose-dep. Variable Characteristics of a Cancer • Uncontrolled growth – beyond normal hyperplasia in vivo – loss of cell-cell inhibition in vitro – anaplasia (highly variable) – apoptosis (normal cell death) defective • Tendency to invade surrounding tissue • Tendency to travel beyond site of origin – metastasis may occur late Early Theories of Carcinogenesis • Surfeit of black bile (Hippocrates) • Omnis cellula ex cellula (Bichat, Pasteur) • Irritation hypothesis (Virchow) – medicolegal issues – persists as lay theory • Embryonic hypothesis (teratomas, etc.) • Parasitic hypothesis Recent Theories of Carcinogenesis • Chemical carcinogenesis – derived from observations by Pott, 1775 – major line of mechanistic oncology every since • Viral theory of carcinogenesis • Two-stage mechanism of Ca.genesis – two processes: initiation, promotion – followed by progression Steps in Chemical Carcinogenesis 1. 2. 3. 4. 5. 6. 7. Biotransformation Initiation: Covalent binding to DNA Fixation: Mutation stabilized by mitosis Gene expression, transformation Neoplastic growth, proliferation Progression, local effects Metastasis Initiation - 1 • Biotransformation: – procarcinogenultimate carcinogen • Interaction with macromolecules – silent binding to other receptors • covalent binding to critical DNA sites – repairnormal cell + DNA adducts – cytotoxicity – fixationinitiation Initiation - 2 • Induced transcription errors • DNA polymerase • Binding to oncogenes – regions of genome that code for cell growth and differentiation – may result in cell transformation • Binding to tumour suppressor genes – apoptosis Oncogenes - 1 • Oncogenes are activated, unregulated versions of protooncogenes • Protooncogenes normal genes encoding for protein kinase and other growth signals • Their gene products stimulate cell growth • Viral oncogenes are altered copies of protooncogenes • 20% of human tumours show oncogenes Oncogenes - 2 • Single copies of oncogenes are sufficient to result in malignant transformation • Oncogene products are convenient biomarkers of effect • Thought by some to be underlying mechanism (distinct from cause) of all Ca Tumour Suppressor Genes • Genes that block neoplastic growth, e.g. p53 • Functional opposites of oncogenes, hence originally named anti-oncogenes • Very difficult to identify and characterize • Characteristic double allelic activity: – both alleles must be damaged for malignant activity – retinoblastoma follows “two hit” model InitiationPromotion - 1 • Cell affected by Ca.gen must replicate for Ca to occur • Cell division fixes the mutation in daughter cells • Promoters induce rapid tissue growth – irritation or necrosis – hyperplasia and stimulate growth • Fixation occurs when mutation is passed on InitiationPromotion - 2 • Initiator = Carcinogen • Cocarcinogen interacts with initiator, may be an initiator itself • Promoter acts at same time or after initiator, is not (usually) initiator alone at dosage at which it promotes Initiation by Physical Means • Ionizing radiation – h + O2free radicalsDNA damage • Nonionizing radiation – UV between 280 - 320 nmpyrimidine dimers? • Epigenetic Ca.gens: Asbestos, silica, foreign bodies Initiation by Biological Agents • Human viral pathogens – oncogenic retroviruses (HIV) – DNA viruses (Epstein-Barr, HSV-2, papilloma, HBV) • Bacteria, biotransformation • Endoparasites (Schistomsoma spp.) Promotion - 1 • “Incomplete” carcinogen requires a promoter • “Complete” carcinogen both initiates and promotes • Stimulation of cell division for fixation • Not genotoxic • Dose-dependent, may have threshold Promotion - 2 • Promoters induce small foci of “preneoplastic” proliferation where transformed cells reside in tissues • Selection pressure favours more rapidly proliferating foci • At high concentrations, cytotoxic promoters may inhibit carcinogenesis by negative selection pressure on susceptible cells Promoters - 3 • Promoters are mitogens, may be endogenous as well as exogenous – hormones (estrogen, prolactin, thyroxin) • Exogenous promoters – phorbol esters (experimental) – phenobarbital – foreign bodies – aromatic hydrocarbons (also initiators) – dioxin (most potent in animal studies) Progression • Proliferation of successful clone • Adaptive growth • Dormancy period in many cases, ends for many reasons (hormonal, nutritional, lymphokines, immunodeficiency etc.) • Tumour vascularization, angiogenesis • Develops into detectable tumour Predisposing Factors - Genetic • Metabolism, biotransformation • Rare AuD cancers – familial polyposis straight AuD) – retinoblastoma (two hit model) • Predisposition to initiation • Inaccurate repair mechanisms • Immunodeficiency Predisposing Factors - Dietary • • • • • Caloric intake Protein deficiency, high fat Carotenes and retinoids - deficiency Tocopherols - deficiency Selenium (glutathione peroxidase) deficiency • Zinc deficiency • Flavanoids (enzyme inhibition) deficiency
