ANTIGENIC PHENOTYPES COMMON TO RAT OVAL CELLS, PRIMARY HEPATOCELLULARCARCINOMAS AND DEVELOPING BILE-DUCTS

The shared expression of monoclonal antibody-defined antigens by oval cells and by bile ducts, neoplastic nodules and primary hepatocellular carcinomas (PHC) has provided support for the ability of oval cells t o undergo differentiation along ductular or hepatocyte lineages and/or to progress to hepatocellular carcinoma, With the aim of obtaining ad ditional insight into this process, nle have combined serial section a nd double labeling immunofluorescence analysis to determine if phenoty pes expressed in vitro by four rat oval cell lines and the H5D.61 hepa tocellular carcinoma cell line and in situ by ethionine-induced primar y hepatocellular carcinomas reproduce antigenic patterns occurring dur ing normal liver development, Analysis using monoclonal antibodies spe cific for the oval cell antigens OV6 and OC,2 and hepatocyte markers H BD.1 and H,4 defined subpopulations in four oval cell lines and neopla stic hepatocytes in PHC and H5D,61 with OC,2-/OV6+ and OC.2+/OV6+ phen otypes. Cells with an OC2+/OV6- phenotype were rarely observed in cell lines or primary tumors, In contrast, areas composed of OV6+/H,4+ cel ls were frequently found in PHC, Examination of fetal and neonatal rat livers demonstrated the stage-specific appearance of three of these p henotypes during liver development. The OC,2+/OV6- phenotype appeared transiently prior to embryonic day (ED) 18 in a subpopulation of HBD,1 + hepatoblasts, OV6 expression was first detected at ED18 on developin g bile ducts that were negative for OC,2, These newly formed ducts rap idly acquired OC,2, starting with ducts in the hilar region and spread ing outward towards the periphery, This OC,2 expression gradient persi sted in the newborn rat liver but became more skewed towards doubly po sitive cells, with OC,2-/OV6+ cells being found primarily in the perip hery, Hepatocytes expressing both OV6 and H.4 mere not observed in fet al liver but appeared in neonatal liver in close proximity to OV6+ int erlobular ducts, From these findings, it was concluded that oval cells and PHC display phenotypes representing normal stages in liver develo pment, suggesting that oval cells and cells within ethionine-induced P HC are capable of initiating but are unable to complete pathways of he patocytic or biliary differentiation.