Histologic Characterization of Hepatic Carcinogenesis in Transgenic Mice Expressing SV40 T-antigens

Abstract

The development of hepatic neoplasms was histologically characterized in transgenic mice that expressed an albumin enhancer-promotor/SV40 T-antigen fusion gene. At least five transgenic and three control mice were examined at monthly intervals over a 3-month period. At 1 month of age, five transgenic mice (two male, three female) and three controls (one male, two female) were examined. Five transgenic mice (two male, three female) and three controls (one male, two female) were examined at 2 months of age. Fourteen transgenic mice (12 male, two female) and three controls (two male, one female) were examined at 3 months of age. At 1 month of age, liver-to-body weight ratios of transgenic mice were increased nearly twofold as compared with controls. Histologically, livers from transgenic mice were characterized by dysplastic hepatocytes with marked variation in nucleus and cell size. At 2 months of age, livers from transgenic mice were 2.5 times larger than control livers and contained numerous 1–5-mm cystic spaces. Transgenic livers also contained multiple eosinophilic, basophilic, and clear foci, as well as cystic, hyperplastic bile ducts and biliary adenomas. At 3 months of age, transgenic livers were enlarged over eightfold as compared with controls and contained numerous cysts and solid masses up to 2 cm in diameter. Trabecular, glandular, and anaplastic hepatocellular carcinomas, as well as benign and malignant biliary neoplasms, were diagnosed. No metastasis was observed. Subcutaneous trabecular hepatocellular carcinomas developed in two of three syngeneic mice that had received transplants of a solid hepatic neoplasm, confirming the neoplastic behavior of these tumors. These experiments, in which viral oncogene expression is targeted to all hepatocytes, support the multistage hypothesis of tumor development and illustrate the similarities in morphologic response of liver to a variety of carcinogenic insults.