Cancer 1

Cancer 1

1. How do you get cancer?

   • Spontaneous mutation
   • Induced Mutation
     • Excessive sunbathing/increased UV exposure
       • Melanoma
     • Cigarette Smoking/benzopyrene
       • Lung cancer

2. Carcinogen

   • Any agent capable of causing cancer in humans or animals
   • Types
     • Physical
       • UV exposure
       • Ionising radiation
     • Biological
       • Viruses
         • HIV
       • Bacteria
         • H. pylori
       • Parasites
         • Liver flukes
     • Chemical
       • Alkylating agents

3. Mutagen

   • A chemical or physical agent that interacts with DNA to promote the appearance of the mutation

4. Ames Test

   • based on histidine biosynthesis
   • Assumes that any substance that is mutagenic may also turn out to be a carcinogen
     • Not always true
   • the test uses a strain of salmonella that carries a mutant gene rendering it unable to synthesis histidine
   • This mutation may be reversed by a potential mutagen with the gene regaining its function
     • Can grow on His- medium
   • Many carcinogens are unreactive with DNA
     • Therefore they are not mutagens
     • E.g. PAH carcinogens are chemically unreactive with DNA making them non-mutagenic in bacteria
       • but in mammals they are substrates for detoxifying enzymes
       • Enzymatic oxidation converts PAHs to electrophilic reagent.
         • form adducts with DNA which in turn generate mutations after replication
   • add liver microsomes
     • Detoxify
     • simulates metabolism
   • If the cells grow the mutations has be rescued and the mutagen is also a carcinogen

5. Animal Experiments

   • Nude mice
     • Highly immunodeficient
   • initiate tumours
     • Painting skin with carcinogens e.g. PAHs
   • Initiate tumour development
     • Order is important
       • initiation then promotion
         • Tumours

6. Tumour initiation

   • carcinogen that sows the seeds of cancer
     • Usually without giving rise to the tumour itself

7. Initiation

   • Irreversible DNA damage in critical gene

8. Tumour Promotor

   • agents which when introduced to a susceptible organism which has already been exposed to an initiator, increase tumour proliferation

9. Promotion

   • Expansion of initiated cells

10. Cell Culture

    • Normal Tissue
      • finite number of divisions
        • Human only divide for 9 months
          • Reaches senescence = Hayflick limit
        • Telomere shortening
          • possible countdown mechanism
          • telomeres shorten with each division
            • become too short and cannot replicate
          • Cells become old
            • Apoptosis can be initiated
      • Require hormone like growth factors
      • Need to spread on Surface
    • The Hayflick Phenomenon
      • Cellular Senescence
        • Intrinsic counting mechanism that could the number of cell divisions
      • 1960s - Leonard Hayflick
        • Suggests that norma human cells are mortal
      • Finite number of passages
        • About 50
    • Normal tissue will attach and spread on ECM protein
      • If not provided with sufficient areas to spread
        • Normal fibroblasts arrest in G1/S restriction point
        • Epithelia cells apoptose
    • Loss of anchorage Dependance
      • required for cells to spread on ECM protein
      • invivo loss of this characteristic may contribute to metastatic capability of tumour cells
      • can be tested experimentally
        • investigating the ability of cells to form colonies in soft agar
        • Tumour cells form colonies in the soft agar
    • Serum
      • provides factors that allow cells to pass G1/S restriction point and multiply
        • Confluent monolayer
      • Serum requirement almost abolished in tumour cell lines
    • Transformation
      • When cultured cells become able to divide infinitely and undergo various other changes characteristic of tumour cells
      • Much higher cell density
      • Poorer Spread
      • Colonies form in soft agar
      • Grow in very low serum
      • Typically highly tumourgenic

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