Mechanisms of multistep carcinogenesis and carcinogen risk assessment

Our plain-English summary of Mechanisms of multistep carcinogenesis and carcinogen risk assessment, by J.C. Barrett (Environmental Health Perspectives, 1993).

The study

• Author: J.C. Barrett
• Journal: Environmental Health Perspectives
• Published: 1993;100:9-20
• Type of article: Review
• Cited by: 165 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Many different types of chemical exposures can increase the incidence of tumors in animals and humans, but usually a long period of time is required before the carcinogenic risk of an exposure is manifested. Both of these observations can be explained by a multistep/multigene model of carcinogenesis. In this model, a normal cell evolves into a cancer cell as the result of heritable changes in multiple, independent genes. The two-stage model of initiation and promotion for chemical carcinogenesis has provided a paradigm by which chemicals can act by qualitatively different mechanisms, but the process of carcinogenesis is now recognized as more complex than simply initiation and promotion. Even a three-stage model of initiation, promotion, and progression, which can be operationally defined, is not adequate to describe the carcinogenic process. The number of genes altered in a cancer cell compared to a normal cell is not known; recent evidence suggests that 3-10 genetic events are involved in common adult malignancies in humans. Two distinct classes of genes, protooncogenes and tumor-suppressor genes, are involved in the cancer process. Multiple oncogenes may be activated in a tumor, while multiple tumor-suppressor genes may be inactivated. Identification of the genes involved in carcinogenesis and elucidation of the mechanisms of their activation or inactivation allows a better understanding of how chemical carcinogens influence the process of neoplastic evolution. The findings of multiple genetic changes (including point mutations, chromosomal translocations, deletions, gene amplification, and numerical chromosome changes) in activated protooncogenes and inactivated tumor-suppressor genes provide experimental support for Boveri's somatic mutation theory of carcinogenesis. In addition to mutagenic mechanisms, chemicals may heritably alter cells by epigenetic mechanisms and enhance the clonal expansion of altered cells. Most chemical carcinogens operate via a combination of mechanisms, and even their primary mechanism of action may vary depending on the target tissues. The classification of chemicals by mechanism of action or by nongenotoxic or genotoxic activity has certain inherent difficulties because no classification of chemicals is exhaustive or definitive.

In plain English

This 1993 article was a review, not a new study. The author drew on published animal, cell-culture and human research to describe cancer as a multistep process in which a normal cell becomes a cancer cell through changes in several genes. It cited estimates of as many as 10 or more mutational changes in adult human cancers. A section on asbestos noted that asbestos and other mineral fibers are usually called nongenotoxic because they are inactive in short-term tests, especially gene mutation tests. The author reviewed evidence that asbestos may act as a promoter, including a synergistic interaction with smoking for lung cancer risk, but noted that this finding could be explained in other ways. Cited evidence for an initiating role included:

• human epidemiological data suggesting asbestos acts early in mesothelioma formation;
• laboratory findings that asbestos causes chromosomal changes in mammalian cells;
• findings that long, thin fibers transformed hamster cells more effectively than short, thick ones;
• findings that most asbestos-transformed hamster cells carried an extra chromosome 11.

The author concluded that both cell proliferation and chromosomal changes are probably involved in asbestos carcinogenicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published evidence on mechanisms of chemical carcinogenesis and their implications for risk assessment; no new data were collected
• Who was studied: No study population. The article discusses published animal, cell-culture and human evidence on chemical carcinogens, including the International Agency for Research on Cancer (IARC) group 1 human carcinogens
• Exposure: Chemical carcinogens in general. Asbestos and other mineral fibers are discussed as one of two classes generally inactive in mutagenicity assays, the other being hormones. No specific asbestos fiber types are named.
• Main results:
  • The review cited estimates that as many as 10 or more mutational changes may occur in adult human cancers.
  • Asbestos and other mineral fibers are generally described as nongenotoxic carcinogens because they are inactive in short-term tests, particularly gene mutation tests.
  • The review cited a synergistic interaction between asbestos exposure and smoking for lung cancer risk in humans, a finding that has been used to argue that asbestos acts as a promoter.
  • The author argued that the smoking interaction could equally be explained by asbestos acting as the initiator and smoking as the promoter.
  • Cited epidemiological data in humans suggest asbestos acts at an early stage in mesothelioma formation, which the author described as consistent with an initiation effect.
  • Although asbestos is inactive as a gene mutagen, cited work shows it induces chromosomal mutations (aneuploidy and aberrations) in many mammalian cell types, including mesothelial cells in culture.
  • In Syrian hamster embryo cells, long, thin fibers induced cell transformation more effectively than short, thick fibers.
  • The proposed mechanism is that fibers taken up by cells physically interfere with chromosome separation during cell division.
  • Trisomy of chromosome 11 (an extra chromosome 11) was observed in the majority of hamster cells transformed by asbestos.
  • On whether some chemicals have dose thresholds, the author's view was that no generalizations can be made and each chemical needs separate analysis.
• The authors' conclusion: The author concluded that both the induction of cell proliferation and the chromosomal changes that follow are probably involved in asbestos carcinogenicity.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Carcinogenic, Translocation, Somatic Mutation.

Related studies

• Environmental factors as regulators and effectors of multistep carcinogenesis — T. Minamoto, M. Mai, et al. (1999)
• Induction by asbestos fibers of anaphase abnormalities: mechanism for aneuploidy induction and possibly carcinogenesis — T.W. Hesterberg, J.C. Barrett (1985)
• Implications of multiple mechanisms of carcinogenesis for short-term testing — B.L. Harper, D.L. Morris (1984)
• Investigating cancer risks related to asbestos and other occupational carcinogens — J. Siemiatycki (2007)
• Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis — H. Ohshima, H. Bartsch (1994)
• Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis — I. Emerit (1994)

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