Carcinogenesis

1. Carcinogenesis Tee L. Guidotti Dept. of Environmental and Occupational Health GWUMC

2. Characteristics of Toxicological Mechanisms

3. 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

4. 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

5. 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

6. Steps in Chemical Carcinogenesis 1. Biotransformation 2. Initiation: Covalent binding to DNA 3. Fixation: Mutation stabilized by mitosis 4. Gene expression, transformation 5. Neoplastic growth, proliferation 6. Progression, local effects 7. Metastasis

7. Initiation - 1 • Biotransformation: • procarcinogenultimate carcinogen • Interaction with macromolecules • silent binding to other receptors • covalent binding to critical DNA sites • repairnormal cell + DNA adducts • cytotoxicity • fixationinitiation

8. 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

9. 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

10. 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

11. 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

12. InitiationPromotion - 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

13. InitiationPromotion - 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

14. Initiation by Physical Means • Ionizing radiation • h + O2free radicalsDNA damage • Nonionizing radiation • UV between 280 - 320 nmpyrimidine dimers? • Epigenetic Ca.gens: Asbestos, silica, foreign bodies

15. Initiation by Biological Agents • Human viral pathogens • oncogenic retroviruses (HIV) • DNA viruses (Epstein-Barr, HSV-2, papilloma, HBV) • Bacteria, biotransformation • Endoparasites (Schistomsoma spp.)

16. 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

17. 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

18. 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)

19. 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

20. Predisposing Factors - Genetic • Metabolism, biotransformation • Rare AuD cancers • familial polyposis straight AuD) • retinoblastoma (two hit model) • Predisposition to initiation • Inaccurate repair mechanisms • Immunodeficiency

21. 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