BIOL 4370_5370 Chapter 8_9_2024(1)

Chemical Carcinogenesis by Amie K. Lund, Ph.D.

Introduction to Carcinogenesis

• Cancer is a disease characterized by cellular mutation, proliferation, and aberrant cell growth.

• Carcinogen: Agent associated with an increased incidence of neoplasms in specific tissues following exposure in animal and/or human studies.

Multistage Carcinogenesis

• Involves a series of stages that are reproducible across various studies and exposures:

  • Initiation: The first step where DNA damage occurs.

  • Promotion: Proliferation of initiated cells.

  • Progression: Transition to neoplastic lesions.

Stages of Carcinogenesis

• Initiation:

  • Process includes DNA repair mechanisms.

  • Changes may lead to initiated cells.

• Promotion:

  • Involves the formation of preneoplastic lesions.

  • Influenced by both endogenous and exogenous tumor promoters.

  • Can be reversible.

• Progression:

  • Transforms benign lesions into malignant tumors.

  • Associated with irreversible changes such as chromosomal translocations.

Mechanisms of Carcinogenesis

• Initiation:

  • Involves stable, heritable changes due to exposure to initiators that cause DNA alterations like mutations.

• Proto-oncogenes and Oncogenes:

  • Oncogenes result from mutations in proto-oncogenes which regulate cell division, often leading to overstimulation of cell growth.

• Tumor Suppressor Genes:

  • When functioning correctly, these genes inhibit cell division under unfavorable conditions. Mutations deactivate this function.

Carcinogenesis: Promotion Stage

• Initiated cells proliferate leading to preneoplastic lesions termed during this phase.

• Tumor promoters typically exhibit organ-specific effects and may be reversible if removed.

Carcinogenesis: Progression Stage

• This stage denotes an irreversible conversion of preneoplastic lesions into full-blown neoplasia (cancer).

• Characterized by rapid cell division and further genetic damage.

Mechanisms of Chemical Carcinogenesis

• Genotoxic Carcinogens:

  • Directly interact with DNA and induce mutations.

  • Include highly reactive molecules that bind to cellular macromolecules.

• Non-genotoxic Carcinogens:

  • Require metabolic activation to exert carcinogenic effects. They usually act at the target tissue where metabolized, referred to as procarcinogens.

DNA Repair Mechanisms

• Various processes exist to repair DNA damage:

  • Base repair: Fixing single base mismatch.

  • Excision repair: Removes chemically altered bases.

  • Non-homologous end joining: Repairs double-strand breaks.

Classes of Genotoxic Carcinogens

• Polyaromatic Hydrocarbons (PAH): Commonly found in smoke and cooked foods.

• Alkylating Agents: Highly reactive with DNA, often seen in pollutants.

• Aromatic Amines and Amides: Form DNA adducts and are found in dyes and drugs.

Mutations and Tumor Development

• The number of mutations and the functional state of tumor suppressor proteins influence the formation of benign versus malignant tumors.

Inorganic Carcinogens

• Carcinogenic potential of several metals such as Arsenic, Beryllium, Cadmium, Chromium, and others, each associated with specific types of tumors.

Nongenotoxic (Epigenetic) Carcinogens

• These types do not directly interact with DNA but result in tumor formation via

  • Cytotoxic effects

  • Receptor-mediated pathways

  • Hormonal pathways

  • DNA methylation

  • Oxidative stress.

Testing for Carcinogenicity

• In vitro and In vivo Assays: Involve various methods to quantify mutagenic potential and assess biological effects.

• Tests such as the Ames test and transgenic rodent assays evaluate mutagenicity following exposure to potential carcinogens.

Conclusion

• Factors influencing cancer induction in humans include lifestyle, occupational exposures, and medical therapies. Different agents are classified by the IARC into groups based on their carcinogenicity to humans.