Carcinogenesis

Tee L. GuidottiDept. of Environmental and

Occupational Health

GWUMC

Characteristics of Toxicological Mechanisms

Carcinog. Immune ToxicityTarget Genome Immune ReceptorThres-hold

? NoThreshold

Recog-nition

Threshold,dose-dep.

Outcome Stereotyp Stereotyp MultipleResponse Stochastic Nonstoch. Dose-dep.Latency Long Short 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. 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

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