Carcinogenesis

Sections

Multistep model of carcinogenesis
Initiation, Promotion, & Progression
Full-Length Text
References

Multistep model of carcinogenesis

Cancers arise from the stepwise accumulation of mutations.

• Initiation, Promotion, & Progression

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 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.

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.

Immunodeficiencies leave patients more susceptible to cancers caused by oncogenic viruses; for example, lymphomas are associated with deficiencies in T-cell immunity.

Precursor lesions can progress to cancer in some cases. Such lesions may be detectable in screenings, and early treatment may reduce the risk that they progress to cancer.

Examples of precursor lesions:

Bronchial mucosa: Inflammatory metaplasia in the bronchial mucosa; this can occur as the result of smoking.
Learn more about lung cancer.

Endoemtrium: Non-inflammatory hyperplasia of the endometrium, which is result of continuous estrogen stimulation.
Learn more about uterine cancer.

Colon: Villous adenomas, which are benign neoplasms in the colon; unlike most other benign neoplasms, villous adenomas progress to cancer in about 50% of cases.

Learn more about colon cancer.

Initiation, Promotion, & Progression

INITIATION

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":

Characteristics of initiating agents:
They are carcinogens
Produce electrophiles (electron-deficient atoms that react with DNA, RNA, and proteins)
Bind DNA to form adducts
Mutagens
Initiating actions are irreversible
Activities are additive.

Carcinogens can be chemical, microbial, or physical.

Chemical initiators
Most common initiators, 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
UV rays, which are associated with squamous cell carcinoma.
Other examples include electromagnetic and particulate radiations.

PROMOTION

Clonal Expansion

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.

Tumor Formation

As a result of clonal expansion, a tumor forms; it can be either benign or pre-neoplastic.

Promoting Agents

Characteristics of promoting agents: they 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.
Promoters act as mitogens; that is, they promote cell division.
Some agents can act as both initiators AND promoters.

Examples of promoters include: hormones and growth factors; phorbol esters; and products of chronic inflammation.

ADDITIONAL DRIVER MUTATIONS

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
• Iinvasion 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 and 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 cancer sites:

Female breast
Prostate
Lungs and bronchi
Colon and rectum
Uterus,
Melanomas of the skin
Urinary bladder
Non-Hodgkin lymphoma
Kidney
Thyroid Gland

Full-Length Text

• Here we will learn about carcinogenesis, which is the process of tumor initiation.

• To begin, start a table, and denote that in the multistep model of carcinogenesis, cancers arise from the stepwise accumulation of mutations.

• Denote that 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).

Let's begin our diagram with a brief look at genetic and acquired factors.

We'll begin with 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.

Next, consider some acquired predisposing factors:

• Chronic infection 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.

• Finally, write that 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.

Let's see 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.

Now, let's turn our attention to the process of carcinogenesis:

• To begin, draw an arrow and indicate three key steps: Initiation, Promotion, and Progression.

• At the start of the arrow, indicate that 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";

• Write that 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.

• Next, write that carcinogens can be chemical, microbial, or physical.

• Chemical types 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.

Next, write that microbial initiators include:

• 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;
• And, as mentioned earlier, the bacterium H. pylori, which is associated with gastric cancers.

• Finally, write that physical initiators include UV rays, which are associated with squamous cell carcinoma; other examples include electromagnetic and particulate radiations.

• Next, indicate that 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 to the initiation event.

• As a result, a tumor forms; show that it can be either benign or pre-neoplastic.

• Write that, in contrast to initiators, 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.

• However, write that some agents can act as both initiators AND promoters.

• Then, indicate that 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.

• Now, indicate that 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.

• Finally, show that progression comprises genetic evolution such that selection for aggressive cancer cell phenotypes ultimately produces a malignant tumor;

• Indicate that, unlike the benign tumor we drew in the promotion stage, this malignant tumor is genetically heterogeneous.

• Write that 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.

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Images:

• Histology (Mark Braun, MD: http://medsci.indiana.edu/c602web/602/c602web/toc.htm)
• Endometrial Hyperplasia (Ed Uthman).
• Villous adenoma (Ed Uthman).
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