Novikoff P M, Ikeda T, Hixson D C, Yam A
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
Am J Pathol. 1991 Dec;139(6):1351-68.
Numerous hepatic cell lineage pathways have been proposed for the development of hepatocarcinogensis induced by chemical carcinogens in rats. The roles of bile ductule cells and hepatocytes in the development of carcinogenesis were investigated using light and electron microscopic procedures to detect differences in morphology and in the phenotypic expression of antigens that are associated with each cell type. In early stages of hepatocarcinogenesis (4-10 weeks after initiation of feeding of a choline-deficient ethionine containing diet), both bile ductulelike (BDL) cells and hepatocytes were seen in mitosis. At the light microscope level, BDL cells showed intense cytoplasmic pyronin (RNA) staining and were positive for the antigens defined by monoclonal antibody 270.38 (bile ductule cells and "oval" cell marker) and glutathione-S-transferase (Yp isoform), whereas hepatocytes were positive for the antigens defined by monoclonal antibodies 270.26 and 258.26 (liver parenchymal cell markers), catalase activity (peroxisome marker) and adenosine triphospatase activity (bile canalicular marker). The authors frequently encountered BDL cells and hepatocytes in close proximity. Ultrastructural examination showed extensive plasma membrane appositions between a subset of BDL cells and hepatocytes. Desmosome structures, tight junctions, microvilli interdigitations and ATPase-positive bile canalicularlike structures were present along the contiguous plasma membrane domains of BDL cells and hepatocytes. Many of the BDL cells attached to hepatocytes were also attached to other BDL cells that had retained a basal lamina. In many cases, BDL cells connected to both hepatocytes and other BDL cells were no longer completely surrounded by basal lamina and had acquired a dual polarity as a consequence of their sharing apical and lateral membrane domains with both BDL cells and hepatocytes. BDL cells showed increased numbers of microperoxisomes (catalase positive organelles) and numerous free ribosomes. Hepatocytes showed a prominent development of the smooth endoplasmic reticulum, a feature prominent in hepatocytes within hyperplastic nodules. Since BDL cells and hepatocytes proliferate and BDL cells and hepatocytes develop intercellular junction sites, the authors propose that both cell types in early stages of carcinogenesis have the capacity to enter the cell lineage pathway leading to the development of hepatocarcinoma. Furthermore, the finding that BDL cells and hepatocytes form multiple attachment sites at the level of the plasma membrane, suggests the possibility that at some stage convergence of separate hepatic cell pathways may occur.
关于大鼠化学致癌物诱导肝癌发生过程中众多肝细胞谱系途径已被提出。利用光学和电子显微镜技术研究胆小管细胞和肝细胞在致癌过程中的作用，以检测与每种细胞类型相关的形态学差异和抗原表型表达差异。在肝癌发生的早期阶段（开始喂食含胆碱缺乏的乙硫氨酸饮食后4 - 10周），可见胆小管样（BDL）细胞和肝细胞均处于有丝分裂状态。在光学显微镜水平，BDL细胞显示强烈的胞质派洛宁（RNA）染色，并且对单克隆抗体270.38（胆小管细胞和“卵圆”细胞标志物）和谷胱甘肽 - S - 转移酶（Yp同工型）所定义的抗原呈阳性反应，而肝细胞对单克隆抗体270.26和258.26（肝实质细胞标志物）、过氧化氢酶活性（过氧化物酶体标志物）和三磷酸腺苷酶活性（胆小管标志物）所定义的抗原呈阳性反应。作者经常遇到紧密相邻的BDL细胞和肝细胞。超微结构检查显示一部分BDL细胞与肝细胞之间有广泛的质膜并列。在BDL细胞和肝细胞相邻的质膜区域存在桥粒结构、紧密连接、微绒毛交错以及ATP酶阳性的胆小管样结构。许多附着于肝细胞的BDL细胞也附着于其他保留基膜的BDL细胞。在许多情况下，连接肝细胞和其他BDL细胞的BDL细胞不再完全被基膜包围，并且由于它们与BDL细胞和肝细胞共享顶端和侧面膜结构域而获得了双极性。BDL细胞显示微过氧化物酶体（过氧化氢酶阳性细胞器）数量增加以及大量游离核糖体。肝细胞显示滑面内质网显著发育，这是增生性结节内肝细胞的一个突出特征。由于BDL细胞和肝细胞增殖以及BDL细胞与肝细胞形成细胞间连接部位，作者提出致癌早期阶段的这两种细胞类型都有能力进入导致肝癌发生的细胞谱系途径。此外，BDL细胞和肝细胞在质膜水平形成多个附着位点这一发现，提示在某个阶段可能发生不同肝细胞途径汇聚的可能性。
