Carcinogenesis

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Carcinogenesis

• Tee L. Guidotti
• Dept. of Environmental and Occupational Health
• GWUMC

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Characteristics of Toxicological Mechanisms
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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Initiation by Biological Agents

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

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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

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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

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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)

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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

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Predisposing Factors - Genetic

• Metabolism, biotransformation
• Rare AuD cancers
• familial polyposis straight AuD)
• retinoblastoma (two hit model)
• Predisposition to initiation
• Inaccurate repair mechanisms
• Immunodeficiency

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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