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 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 - 1

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