Multistep model of carcinogenesis

• Cancers arise from the stepwise accumulation of mutations.
• Cancer development depends on predisposing and environmental factors, age, and other influences; furthermore, these variables have synergistic effects (for example, it appears that alcohol and tobacco act together to increase risk of certain cancers).

Genetic and acquired factors

Genetic mutations:

— Some mutations lead to loss-of-function in tumor suppressor genes; for example, a dysfunctional APC gene is associated with colon cancer.
— Mutations can also lead to oncogenic gain-of-function or gene amplification. For example, translocation and subsequent amplification of the MYC oncogene is associated with Burkitt Lymphoma.

Examples of acquired predisposing factors:

• Chronic infection and inflammation promotes increased cell turnover, metaplasia, and other pre-cancer events; for example, infection by Helicobacter pylori and the ensuing inflammation can lead to gastric cancer.
• Individuals with immunodeficiencies are more susceptible to cancers caused by oncogenic viruses; for example, lymphomas are associated with deficiencies in T-cell immunity.
• Some precursor lesions can progress to cancer. Such lesions may be detectable in screenings, and early treatment may reduce the risk that they progress to cancer.
  — Some histological samples of precursor lesions:
  • In our first sample, we see an example of inflammatory metaplasia in the bronchial mucosa; this can occur as the result of smoking.
  • In the next image, we see an example of non-inflammatory hyperplasia of the endometrium, which is result of continuous estrogen stimulation.
  • Finally, we see villous adenomas, which are benign neoplasms in the colon; unlike most other benign neoplasms, villous adenomas progress to cancer in about 50% of cases.

Carcinogenesis:
Three key steps: Initiation, Promotion, and Progression.

Initiation

• Occurs when the first driver mutation induces permanent non-lethal DNA damage to a cell.
  — Because the first driver mutation initiates the process of carcinogenesis, the agents responsible are called “initiators”:
• Initiating agents are carcinogens; they produce electrophiles (electron-deficient atoms that react with DNA, RNA, and proteins); they bind DNA to form adducts; they are mutagens; their initiating actions are irreversible; and, their activities are additive.
• Carcinogens can be chemical, microbial, or physical.

Chemical initiators

• Are by far the most common, comprising about 90% of all carcinogens; they can be indirect-acting or direct-acting.
• Indirect-acting carcinogens require metabolic activation.
  — Examples include: Polycyclic aromatic hydrocarbons (aka, PAHs), which are released by burning fossil fuels and tobacco; Aflatoxin B1, which is naturally produced by Aspergillus fungi; and, Benzidine, which is a synthetic chemical formerly used to produce dyes; because it is a known carcinogen, it is no longer sold in the U.S.
• Direct-acting chemical carcinogens do not require metabolic activation.
  — Paradoxically, some anticancer drugs fall into this category; Other examples include: dimethyl sulfate, which can be used as a methylating agent, and, diepoxybutane, which was formerly used in industrial settings.

Microbial initiators

• Some strains of the human papillomavirus (HPV) that are associated with oncogenic E6 and E7 proteins.
• Epstein-Barr Virus (EBV), which is associated with the African form of Burkitt Lymphoma.
• Hepatitis B and C, which are associated with liver cancer.
• Bacterium H. pylori, which is associated with gastric cancers.

Physical initiators

• Include UV rays, which are associated with squamous cell carcinoma.
• Other examples include electromagnetic and particulate radiations.

Promotion

• The promotion stage of carcinogenesis comprises clonal expansion, which occurs when promoters induce the proliferation of the DNA-damaged cell. Be aware that this can occur long after the initiation event.
• As a result, a tumor forms; it can be either benign or pre-neoplastic.
• Promoting agents do NOT produce electrophiles, nor do they bind DNA; they are not mutagens; and, their effects are usually reversible. Furthermore, their effects are modulated by diet, hormonal and environmental factors.
• Some agents can act as both initiators AND promoters.
• Promoters act as mitogens; that is, they promote cell division.
• Some examples of promoters include: hormones and growth factors; phorbol esters; and products of chronic inflammation.
• Continued proliferation exposes pre-neoplastic cells to additional driver mutations.
  — These 80+ mutations lead to the acquisition of defining cancer hallmarks, which include: Self-sufficiency and the ability to ignore growth suppressors; evasion of apoptosis and immortality; altered metabolism and angiogenesis to meet nutritional needs; invasion and metastasis into new niches; and, evasion of the host immune system.
  This process can take years, even decades, and helps account for the latent period it takes for some cancers to develop.

Progression

• Progression comprises genetic evolution such that selection for aggressive cancer cell phenotypes ultimately produces a malignant tumor.
• Unlike the benign tumor we drew in the promotion stage, this malignant tumor is genetically heterogeneous.
• Common sites of cancer in men and women in the U.S. include: the female breast, the prostate, lungs and bronchi, colon and rectum, uterus, melanomas of the skin, urinary bladder, non-Hodgkin lymphoma, kidney, and thyroid gland.