Enomoto A, Sandgren E P, Maronpot R R
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Pathol. 1998 Jul-Aug;26(4):570-8. doi: 10.1177/019262339802600414.
Transgenic mice carrying the SV40 T antigen (TAg) gene, which develop hepatocellular and biliary cell tumors by 4 mo of age, show ductular structures in the neonatal liver. Coexpression of c-myc with TAg increases the extent and persistence of ductular lesions and also accelerates tumor development. To analyze possible links between altered gene expression and cell differentiation and to determine the relationship between the ductular structures and tumor development in these mice, ductular cells in single (TAg) and bitransgenic (TAg x c-myc) mice were characterized for biliary and hepatocellular differentiation, transgene expression, and proliferation activity. The results show that the ductular cells in these transgenic mice have characteristics of biliary cells, including basement membrane formation, positive laminin staining, and bile duct-specific lectin (Dolichos biflorus agglutinin and peanut agglutinin) binding, and characteristics of hepatocytes, including albumin expression and ultrastructural features such as round nuclei with 1 or 2 nucleoli and well-developed cytoplasmic organelles. However, differences in transgene expression and cell proliferation between the ductular cells and nonductular hepatocytes were not apparent. Thus, the ductular cells could not be defined as tumor progenitor cells in these mouse livers. However, this model suggests that manipulation of gene expression can alter differentiation of hepatic parenchymal cells.
携带SV40 T抗原（TAg）基因的转基因小鼠在4月龄时会发生肝细胞和胆管细胞肿瘤，其新生肝脏中可见小胆管结构。c-myc与TAg共表达会增加小胆管病变的程度和持续时间，并加速肿瘤发展。为了分析基因表达改变与细胞分化之间的可能联系，并确定这些小鼠中小胆管结构与肿瘤发展之间的关系，对单转基因（TAg）和双转基因（TAg x c-myc）小鼠的小胆管细胞进行了胆管和肝细胞分化、转基因表达及增殖活性的特征分析。结果显示，这些转基因小鼠的小胆管细胞具有胆管细胞的特征，包括基底膜形成、层粘连蛋白染色阳性以及胆管特异性凝集素（双花扁豆凝集素和花生凝集素）结合，同时也具有肝细胞的特征，包括白蛋白表达以及超微结构特征，如具有1或2个核仁的圆形细胞核和发育良好的细胞质细胞器。然而，小胆管细胞与非小胆管肝细胞之间在转基因表达和细胞增殖方面的差异并不明显。因此，在这些小鼠肝脏中，小胆管细胞不能被定义为肿瘤祖细胞。不过，该模型表明基因表达的操控可改变肝实质细胞的分化。
