Clinical Assignment 7 Pathology Question 1

Briefly discuss the mechanisms of carcinogenesis under the following headings:
a) Chemical Carcinogenesis
b) Radiation Carcinogenesis
c) Viral Carcinogenesis
For each of the above, provide a short list of human cancers with these aetiologies.

  • Carcinogenesis
    Carcinogens are classically considered as initiators or promoters (or both). Initiation is required to alter the cell in some way, but by itself does not lead to carcinogenesis. Initiation is usually alteration of DNA (eg. loss of p53), and is permanent. Promoters are agents which stimulate cells to divide, thus leading to possible development of further mutations and cancer. It has been shown that a promoting signal, in the absence of previous initiation, does not lead to cancer formation. Promoters include stimuli that increase cellular proliferation, such as agents causing cellular death in the vicinity. Sex hormones also stimulate some cell populations to divide (eg. breast, prostate).
    • Chemical Carcinogenesis
      Chemical carcinogens typically fit into the classical model of carcinogenesis. They may be directly acting (eg. chemotherapy, which causes DNA damage) or indirectly acting (eg. chemicals in tobacco smoke). Indirectly acting chemical carcinogens are metabolised by the cell prior to causing their damage.
      Initiating chemical carcinogens cause permanent changes in the genome of the cell through DNA damage. If this occurs in a tumour suppressor gene or oncogene, when the cell is subsequently exposed to a promoter (eg. inflammation or a second type of chemical) mutations may progress further and lead to cancer formation.
      Some chemical carcinogens may function as initiators and promoters, usually by causing cellular death in some cells. This leads to inflammation and replication of the neighbouring cells.
      • Examples
        Bladder cancer, lung cancer (esp small cell, squamous cell carcinoma) -> Tobacco smoking
        Leukaemia following chemotherapy for other cancer types.
    • Radiation Carcinogenesis
      Radiation is typically an initiator of carcinogenesis, although inflammation and cell death caused by radiation may also function as a promoter. Initiation by radiation is caused by incompletely repaired DNA damage which may lead to inactivation of tumour suppressors or activation of oncogenes. There is often a significant latency after exposure to ionising radiation and development of malignancy.
      • Examples
        Low, increased risk (stochastic effect) of cancer development in patients exposed to medical radiation.
        Meningioma in patients treated with cerebral irradiation
        Angiosarcoma in women treated for breast cancer
    • Viral Carcinogenesis (Microbial Carcinogenesis)
      Viruses may cause both initiation and promotion. Viruses may attempt to turn off apoptosis or tumour suppressor mechanisms (eg. human papilloma virus, HPV), or alternatively increase expression of native or viral oncoproteins (Epstein-Barr Virus). Alternatively, promotion occurs through the chronic inflammation caused by the hepatitis viruses B and C.
      Helicobacter pyloris is not a virus but may stimulate the development of gastric carcinoma by producing chronic inflammation. Bacterial proteins are also suspected of causing cellular proliferation above the inflammation effects.
      • Examples
        Epstein Barr Virus and nasopharyngeal carcinoma
        Hepatoma and the hepatitis viruses
        Cervical and head and neck squamous cell carcinoma from HPV.
        Gastric carcinoma from chronic helicobacter infection.
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