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
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.