The role of oval cells and gap junctional intercellular communication in hepatocarcinogenesis

The role of oval cells, and Gap functional Intercellular Connunication (GJI C) in hepatic differentiation and neoplasia is controversial Oval cells acc umulate in great number when hepatocyte regeneration is blocked following m assive hepatotoxicity ol after treatment with some hepatocarcinogens. This suggests oval cells are facultative stem cells or close progeny of liver st em cells that are activated only under specific conditions. Studies with ov al cell lines clearly indicate that they can differentiate into hepatocytes and that neoplastic derivatives of oval cells can produce hepatocellular a nd biliary neoplasms. Because hepatocytes express Cx32 and biliary cells ex press Cx43, the differentiation of oval cells into hepatocytes or biliary e pithelium requires expression of one or the other peptide. In addition beca use Cx32 hemichannels and Cx43 hemichannels cannot form heterotypic patent channels, the type of connexin expressed by the differentiating oval cell w ill determine whether it communicates with hepatocytes ol biliary epithelia l 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 a nd cholangiocellular neoplasms. The type of connexin expressed may also det ermine the susceptibility of the differentiating oval cells to the various types of rodent liver tumor promotes. Thus, three major points have been de veloped here. First, Cx32 ol Cx43 expression and GJIC with hepatocytes ol b iliary epithelial cells, respectively, may determine the final differentiat ed fate of oval cells. Secondly, blocked GJIC may determine whether oval ce lls progress to hepatocellular ol cholangiocellular carcinoma. Lastly, the ability of tumor promoters to block Cx32 ol Cx43-mediated GJIC in different iating oval cells may determine whether these agents promote the formation of hepatocellular ol cholangiocellular carcinomas. Thus, GJIC may be the ke y factor in the differentiation of oval cells and blocked GJIC may promote their neoplastic transformation in a lineage-specific manner. In this chapt er; we have outlined several new hypotheses on the role of oval cells and G JIC 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 trut h often arises amidst controversy and may be found in the most peculiar pla ces.