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Non-genotoxic mechanisms of carcinogenesis: studies of cell transformation and gap junctional intercellular
1International Agency for Research on Cancer, Lyon, France.
Abstract:
It is widely accepted that a series of genetic changes accumulate during carcinogenesis. In addition, it is likely that various non-genotoxic mechanisms also operate at different stages of carcinogenesis. It is even possible that non-genotoxic mechanisms indirectly generate genetic changes, e.g., through induction of cell proliferation, active oxygen species or cytosine methylation. This may partially explain why many carcinogens are devoid of activity when tested in the usual genetic toxicology assays. In vitro cell transformation mimics certain stages of in vivo carcinogenesis. It has therefore been proposed that both genotoxic and non-genotoxic aspects of carcinogenesis can be studied in cell transformation systems, with tumor formation by transformed cells in syngenic animals or nude mice as the endpoint. Many genotoxic as well as non-genotoxic carcinogens induce transformation of Syrian hamster embryo, murine Balb/c 3T3 and murine C3H10T1/2 cells; interaction of genotoxic and non-genotoxic mechanisms can be clearly seen in 2-stage cell transformation studies in which a genotoxic initiating agent and a non-genotoxic promoting agent act synergistically to induce transformation of rodent cells. Aberrant control of gap junctional intercellular communication (GJIC) in cell transformation and carcinogenesis is well documented. Possible genotoxic as well as non-genotoxic mechanisms involved in abnormal gap junction communication control in multistage carcinogenesis are discussed.
Insights
Carcinogenesis involves genetic and non-genotoxic mechanisms, potentially interacting. Cell transformation models reveal synergistic effects and altered gap junction communication (GJIC) in multistage cancer development.
Area of Science:
- Cancer research
- Molecular biology
- Toxicology
Background:
- Carcinogenesis is understood to involve accumulating genetic alterations.
- Non-genotoxic mechanisms also play a role in carcinogenesis, potentially influencing genetic changes indirectly.
Purpose of the Study:
- To investigate the interplay of genotoxic and non-genotoxic mechanisms in carcinogenesis.
- To explore the utility of in vitro cell transformation systems for studying both aspects of carcinogenesis.
- To examine the role of aberrant gap junctional intercellular communication (GJIC) in multistage carcinogenesis.
Main Methods:
- Utilized in vitro cell transformation assays with Syrian hamster embryo, Balb/c 3T3, and C3H10T1/2 cells.
- Employed two-stage cell transformation studies with genotoxic initiators and non-genotoxic promoters.
- Investigated mechanisms of abnormal GJIC control in cell transformation and carcinogenesis.
Main Results:
- Demonstrated that both genotoxic and non-genotoxic carcinogens induce cell transformation.
- Observed synergistic effects between genotoxic and non-genotoxic agents in two-stage transformation studies.
- Highlighted the well-documented aberrant control of GJIC in cell transformation and carcinogenesis.
Conclusions:
- In vitro cell transformation systems can model both genotoxic and non-genotoxic carcinogenesis.
- Non-genotoxic mechanisms can indirectly induce genetic changes, explaining carcinogen assay discrepancies.
- Aberrant GJIC control is a significant factor in multistage carcinogenesis, influenced by both genotoxic and non-genotoxic pathways.