Holder J W, Elmore E, Barrett J C
Genetic Toxicology Assessment Branch, EPA, Washington, DC 20460.
Cancer Res. 1993 Aug 1;53(15):3475-85.
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.
间隙连接（GJs）实现了必需代谢物和离子在细胞间的通讯。GJs使组织能够平均响应、清除废物，并通过稀释和允许稳态分解代谢来最小化异生物的影响。许多化学物质会对膜GJ组装产生不利影响，导致GJ细胞间通讯发生可逆性改变。在毒性作用期间，必需代谢物、离子和调节因子无法在整个组织群落中进行稳态共享。代谢回路的改变被认为会中断器官整合。持续性的GJ扰动可导致慢性影响（如癌症），许多肿瘤启动子会抑制GJ细胞间通讯。肝癌前病灶在病灶内部进行通讯（但水平降低），且在病灶边界与正常细胞之间的通讯不当（或根本不通讯）。随着时间的推移，病灶在组织内可能变得调控更少且更加孤立。在肿瘤进展阶段，GJs的数量持续减少，并且在转移过程中可能发生质性改变，因为在原发肿瘤细胞与继发性转移部位的外来宿主细胞之间会形成连接。细胞粘附分子和整合素的细胞分选和结合机制在继发性部位也可能发生改变。这可能会使原发肿瘤细胞在继发性部位通过GJs重新定位并得到滋养。
