Ruch R J, Trosko J E
Department of Pathology, Medical College of Ohio, Toledo 43614, USA.
Anticancer Res. 1999 Nov-Dec;19(6A):4831-8.
The role of oval cells, and Gap Junctional Intercellular Communication (GJIC) in hepatic differentiation and neoplasia is controversial. Oval cells accumulate in great number when hepatocyte regeneration is blocked following massive hepatotoxicity or after treatment with some hepatocarcinogens. This suggests oval cells are facultative stem cells or close progeny of liver stem cells that are activated only under specific conditions. Studies with oval cell lines clearly indicate that they can differentiate into hepatocytes and that neoplastic derivatives of oval cells can produce hepatocellular and biliary neoplasms. Because hepatocytes express Cx32 and biliary cells express Cx43, the differentiation of oval cells into hepatocytes or In addition, because Cx32 hemichannels and Cx43 hemichannels cannot form heterotypic patent channels, the type of connexin expressed by the differentiating oval cell will determine whether it communicates with hepatocytes or biliary epithelial cells, respectively. This communication may be necessary for the further differentiation and regulated growth of the differentiating oval cells and impairment of this GJIC may contribute to the formation of hepatocellular and cholangiocellular neoplasms. The type of connexin expressed may also determine the susceptibility of the differentiating oval cells to the various types of rodent liver tumor promoters. Thus, three major points have been developed here. First, Cx32 or Cx43 expression and GJIC with hepatocytes or biliary epithelial cells, respectively, may determine the final differentiated fate of oval cells. Secondly, blocked GJIC may determine whether oval cells progress to hepatocellular or cholangiocellular carcinoma. Lastly, the ability of tumor promoters to block Cx32 or Cx43-mediated GJIC in differentiating oval cells may determine whether these agents promote the formation of hepatocellular or cholangiocellular carcinomas. Thus, GJIC may be the key factor in the differentiation of oval cells and blocked GJIC may promote their neoplastic transformation in a lineage-specific manner. In this chapter, we have outlined several new hypotheses on the role of oval cells and GJIC in hepatocarcinogenesis. We hope that other investigators will consider our ideas, but realize these views will be contentious to many. Our intent, however, was to stimulate discussion and debate, even argument, because truth often arises amidst controversy and may be found in the most peculiar places.
卵圆细胞以及间隙连接介导的细胞间通讯（GJIC）在肝脏分化和肿瘤形成中的作用存在争议。当大量肝毒性物质作用后或使用某些肝癌致癌物处理导致肝细胞再生受阻时，卵圆细胞会大量积聚。这表明卵圆细胞是兼性干细胞或肝干细胞的紧密后代，仅在特定条件下被激活。对卵圆细胞系的研究清楚地表明，它们可以分化为肝细胞，并且卵圆细胞的肿瘤衍生物可以产生肝细胞和胆管肿瘤。因为肝细胞表达Cx32，胆管细胞表达Cx43，所以卵圆细胞向肝细胞或胆管细胞的分化……此外，由于Cx32半通道和Cx43半通道不能形成异型开放通道，分化中的卵圆细胞所表达的连接蛋白类型将分别决定它是否与肝细胞或胆管上皮细胞进行通讯。这种通讯对于分化中的卵圆细胞的进一步分化和生长调节可能是必要的，而这种GJIC的受损可能促成肝细胞和胆管细胞肿瘤的形成。所表达的连接蛋白类型也可能决定分化中的卵圆细胞对各种类型啮齿动物肝肿瘤启动子的敏感性。因此，这里提出了三个要点。首先，Cx32或Cx43的表达以及分别与肝细胞或胆管上皮细胞的GJIC，可能决定卵圆细胞的最终分化命运。其次，受阻的GJIC可能决定卵圆细胞是否会发展为肝细胞癌或胆管细胞癌。最后，肿瘤启动子在分化中的卵圆细胞中阻断Cx32或Cx43介导的GJIC的能力，可能决定这些试剂是否促进肝细胞癌或胆管细胞癌的形成。因此，GJIC可能是卵圆细胞分化的关键因素，而受阻的GJIC可能以谱系特异性方式促进其肿瘤转化。在本章中，我们概述了关于卵圆细胞和GJIC在肝癌发生中作用的几个新假说。我们希望其他研究者会考虑我们的观点，但要意识到这些观点对许多人来说会有争议。然而，我们的目的是激发讨论、辩论，甚至争论，因为真理常常在争议中浮现，可能在最奇特的地方被发现。
