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  + O 2  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