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Gap Junction Function and Cancer

Genetic Toxicology Assessment Branch, Office of Health and Environmental Assessment, Office of Research and Development (RD-689), EPA, Washington, DC 20460 [J. W. H.]; National Institute for the Advancement of in Vitro Sciences, Irvine, California 92715 [E. E.]; and Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [J. C. B.]

Gap junctions (GJs) provide cell-to-cell communication of essential metabolites and ions. GJs allow tissues to average responses, clear waste products, and minimize the effects of xenobiotics by dilution and allowing steady-state catabolism. Many chemicals can adversely affect the membrane GJ assembly causing reversible alterations in GJ intercellular communication. During toxicity essential metabolites, ions, and regulators are not shared homeostatically throughout a tissue community. Alterations in metabolic circuits are thought to interrupt organ integration. Persistent GJ perturbation can cause chronic effects (e.g., cancer), and many tumor promoters inhibit GJ intercellular communication. Liver precancerous foci intracommunicate (but at a reduced level) and intercommunicate improperly (or not at all) across the foci boundary to normal cells. In time, foci can become less regulated and more isolated within the tissue. GJs remain reduced quantitatively in the tumor progression stage and may be qualitatively altered in metastasis since connections are made between the primary tumor cells and foreign host cells at the secondary metastatic site. Cell sorting and binding mechanisms by the cell adhesion molecules and integrins may also be altered at secondary sites. This may allow the relocation of primary tumor cells and nurturance via GJs at the secondary site.

¹ The views expressed in this paper are those of the authors and do reflect the views or policies of the United States Environmental Protection Agency or the National Institute of Environmental Health Sciences.

² To whom requests for reprints should be addressed, at Genetic Toxicology Assessment Branch, Office of Health and Environmental Assessment, Office of Research and Development (RD-689), United States Environmental Protection Agency, Washington, DC 20460.

Received 12/18/92. Accepted 5/26/93.

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