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Lecture 14 Neoplasia II – Carcinogenesis

1) Know the difference between initiation and promotion and between direct and
   indirect chemical carcinogens.
   Tumor Initiation – an irreversible, additive process involving the single
   subcarcinogenic application of a chemical or physical agent, which may be a direct or
   indirect carcinogen and cannot cause cancer by itself.
   Tumor Promotion – a reversible process involving multiple applications of a
   promoting agent, which is not carcinogenic. Promoters all induce cellular
   proliferation and clonal expantion of initiated cells.
   A complete carcinogen initiates and promotes.
   Direct chemical carcinogens – do not require metabolic action.
   Indirect chemical carcinogens – require metabolism to produce ultimate carcinogen;
   generally performed by the cytochrome P-450 mono-oxygenase system.
2) Know chemical carcinogens that have been associated with specific types of
Chemical Carcinogen                            Types of Cancer
Direct Acting alkylators
Polycyclic aromatic hydrocarbons – found in
cigarette smoke, animal fats, smoked meats
Aromatic amines and Azo dyes                   Liver (normally)
β-napthylamine                                 Bladder (transitional cell carcinoma)
Naturally occurring carcinogens
Aflatoxin B1                                   Hepatocellular carcinoma
Nitrosamines and amides – formed in GI tract
Asbestos                                       Bronchogenic carcinoma, mesothelioma, and
                                               GI carcinoma
Cigarette smoke                                Lung cancer and others
Vinyl chloride                                 Hemangiosarcoma (liver of factory workers)
Metals – Chromium, Nickel                      Lung cancer
3) Know the types of cancer associated with exposure to UV and ionizing radiation.
   a. Ultraviolet Rays
      - UVA (320-400nm) once thought to be harmless; now believed carcinogenic
      - UVB (280-320nm) responsible for risk of squamous cell, basal cell, and
          malignant skin cancer.
      - UVC (200-280nm) mutagenic but filtered by ozone.
   b. Ionizing radiation
      - Electramutagenic: gamma rays, x-rays
      - Particulate – alpha & beta particles, protons, neutrons (A-bomb survivors).
4) Appreciate the role of specific microorganisms (HPV, EBV, HBV, KSHV,
   HTLV1 and helobacter pylori) in carcinogenesis.
   a. Human papillomavirus (HPV) – 85% of invasive squamous cell carcinomas have
      DNA sequences of HPV 16, 18, and 31. HPV-6 and 11 (genital warts) are low
      risk. HPV-16 and 18 act by protein E7 (binds Rb tumor suppressor) and protein
      E6 (binds and helps degrade p53).
b. Epstein Barr virus (EBV) – herpes family virus associated with Burkitt
   lymphoma, B-cell lymphoma in immunosuppressed patients, some Hodgkin
   lymphoma, and nasopharyngeal carcinoma. Binds CD21 receptor.
c. Hepatitis B virus (HBV) – leading carcinogenic virus associated with
   hepatocellular carcinoma through chronic injury and viral proteins (HBx).
d. Kaposi Sarcoma Herpes Virus (KSHV) – causes Kaposi Sarcoma in AIDS
   patients by releasing p53 inhibitors and homologues of IL-6 and cyclin D.
e. Human T-cell leukemia virus type 1 (HTLV1) – associated with T-cell leukemias
   and lymphoma contracted through sex, blood, and breast milk.
f. Helicobacter pylori – associated with gastric carcinoma (>80%), antibiotics
   reduce risk by half.

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