1. Carcinogenesis is a multistage process involving initiation, promotion, and progression. Initiation involves damage to DNA from carcinogens, radiation, or viruses. 2. Promotion stimulates cell division to fix the mutation and select for preneoplastic cells. Common promoters include hormones, phorbol esters, and foreign bodies. 3. During progression the mutated clone proliferates into a detectable tumor through angiogenesis and evading the immune system. Genetic and dietary factors can predispose to cancer development.

1. Carcinogen

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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

15. 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

16. 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

17. 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)

18. 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

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

20. 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