Carcinogenesis

• Three stages of carcinogenesis

  • Initiation: Normal cell DNA --> interact w/ initiator (must be genotoxic carcinogen to bind DNA) --> induce genetic alteration
  • Promotion: initiated cell --> exposed to promoter (repeated application) --> cell proliferation
  • Progression: accumulation of additional irreversible genetic changes; marked by increasing genetic instability + malignancy
• Initiation to promotion

  • The initiated tumor cells may remain dormant (not undergo clonal expansion) for a long period of time before it becomes a tumor through cell proliferation in the presence of promoters
  • The dormancy is probably due to the suppressant influence of the surrounding normal cells exerted through certain intercellular communication
• The suppressant influence can be reduced by:

  • Growth factors (e.g., Phorbol esters)
  • Cell killing (e.g., Cytotoxic chemicals)
  • Inhibition of gap junction intercellular communication (e.g., DDT and phenobarbital)
  • Changes in DNA methylation profile
• • Initiation (Genotoxic): Formation of DNA adducts on proto-oncogenes and/ or tumor suppressor genes --> Mutation
  • Promotion (Non-genotoxic): Increase cell proliferation, Inhibit intracellular communication, DNA methylation profile
  • Progression: Additional genetic and epigenetic changes --> Genomic instability