Hixson D C, Chapman L, McBride A, Faris R, Yang L
Department of Medical Oncology, Rhode Island Hospital, Providence 02902, USA.
Carcinogenesis. 1997 Jun;18(6):1169-75. doi: 10.1093/carcin/18.6.1169.
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 to undergo differentiation along ductular or hepatocyte lineages and/or to progress to hepatocellular carcinoma. With the aim of obtaining additional insight into this process, we have combined serial section and double labeling immunofluorescence analysis to determine if phenotypes expressed in vitro by four rat oval cell lines and the H5D.61 hepatocellular carcinoma cell line and in situ by ethionine-induced primary hepatocellular carcinomas reproduce antigenic patterns occurring during normal liver development. Analysis using monoclonal antibodies specific for the oval cell antigens OV6 and OC.2 and hepatocyte markers HBD.1 and H.4 defined subpopulations in four oval cell lines and neoplastic hepatocytes in PHC and H5D.61 with OC.2-/OV6+ and OC.2+/OV6+ phenotypes. Cells with an OC2+/OV6- phenotype were rarely observed in cell lines or primary tumors. In contrast, areas composed of OV6+/H.4+ cells were frequently found in PHC. Examination of fetal and neonatal rat livers demonstrated the stage-specific appearance of three of these phenotypes 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 developing bile ducts that were negative for OC.2. These newly formed ducts rapidly acquired OC.2, starting with ducts in the hilar region and spreading outward towards the periphery. This OC.2 expression gradient persisted in the newborn rat liver but became more skewed towards doubly positive cells, with OC.2-/OV6+ cells being found primarily in the periphery. Hepatocytes expressing both OV6 and H.4 were not observed in fetal liver but appeared in neonatal liver in close proximity to OV6+ interlobular ducts. From these findings, it was concluded that oval cells and PHC display phenotypes representing normal stages in liver development, suggesting that oval cells and cells within ethionine-induced PHC are capable of initiating but are unable to complete pathways of hepatocytic or biliary differentiation.
卵圆细胞、胆管、肿瘤结节和原发性肝细胞癌（PHC）对单克隆抗体定义抗原的共同表达，为卵圆细胞沿胆小管或肝细胞谱系进行分化和/或发展为肝细胞癌的能力提供了支持。为了进一步深入了解这一过程，我们结合了连续切片和双重标记免疫荧光分析，以确定四种大鼠卵圆细胞系和H5D.61肝癌细胞系在体外表达的表型，以及乙硫氨酸诱导的原发性肝细胞癌在原位表达的表型，是否重现正常肝脏发育过程中出现的抗原模式。使用针对卵圆细胞抗原OV6和OC.2以及肝细胞标志物HBD.1和H.4的单克隆抗体进行分析，确定了四种卵圆细胞系中的亚群以及PHC和H5D.61中的肿瘤肝细胞具有OC.2-/OV6+和OC.2+/OV6+表型。在细胞系或原发性肿瘤中很少观察到OC2+/OV6-表型的细胞。相反，在PHC中经常发现由OV6+/H.4+细胞组成的区域。对胎鼠和新生鼠肝脏的检查表明，在肝脏发育过程中，这些表型中的三种具有阶段特异性出现。OC.2+/OV6-表型在胚胎第18天（ED）之前短暂出现在HBD.1+肝母细胞亚群中。OV6表达在ED18首次在发育中的胆管上检测到，这些胆管对OC.2呈阴性。这些新形成的胆管迅速获得OC.2，从肝门区域的胆管开始，向外向周边扩散。这种OC.2表达梯度在新生大鼠肝脏中持续存在，但向双阳性细胞倾斜得更厉害，OC.2-/OV6+细胞主要位于周边。在胎肝中未观察到同时表达OV6和H.4的肝细胞，但在新生肝中出现在紧邻OV6+小叶间胆管的位置。从这些发现可以得出结论，卵圆细胞和PHC表现出代表肝脏发育正常阶段的表型，这表明卵圆细胞和乙硫氨酸诱导的PHC中的细胞能够启动但无法完成肝细胞或胆管分化途径。
