Hepatocarcinogenesis in Transgenic Mice Carrying Albumin‐promoted SV40 T Antigen Gene

• Published in: Japanese Journal of Cancer Research Vol. 82; no. 11; pp. 1226 - 1233
• Main Authors: Hino, Okio, Kitagawa, Tomoyuki, Nomura, Kimie, Ohtake, Keiko, Cui, Lixin, Furuta, Yasuhide, Shinichi, Shinichi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-1991
• Subjects: Albumin; Animals; Antigens, Polyomavirus Transforming - genetics; Biomarkers, Tumor - analysis; Blotting, Northern; Crosses, Genetic; Female; gamma-Glutamyltransferase - analysis; Glucose-6-Phosphatase - analysis; Hepatocarcinogenesis; Liver - cytology; Liver - microbiology; Liver - pathology; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - microbiology; Liver Neoplasms, Experimental - pathology; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Mitotic Index; Multistep carcinogenesis; Plasmids; Promoter Regions, Genetic; Restriction Mapping; Serum Albumin - genetics; Simian virus 40 - genetics; SV40 T antigen; Transgenic mouse
• ISSN: 0910-5050; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1991.tb01785.x

We have developed transgenic mice that inherit albumin promoter‐regulated simian virus 40 (SV40) large T antigen gene, expressed specifically in hepatocytes. These mice all develop multifocal hepatocellular carcinomas at around 5 months and die of liver insufficiency by 7 months. Sequential morphological observation of hepatocarcinogenesis revealed 5 distinct stages: (I) newborn to 2 weeks of age, neither recognizable histological changes nor cellular replication in spite of T antigen expression; (II) between 3 and 7 weeks, diffuse cytomegalic change of hepatocytes with numerous abnormal mitoses, usually resulting in cell death; (III) from 7 weeks onwards, quasi‐regenerative small hepatocyte foci with a decreased tendency for cytomegaly in spite of T antigen expression, rapidly replacing the hepatic tissue; (IV) 11 weeks of age and thereafter, neoplastic foci and nodules with enzymatic alteration; (V) 20 weeks of age and thereafter, gross hepatocellular carcinomas with occasional pulmonary metastases. Considerable variation existed both in morphological and enzymatic features and T antigen expression among neoplastic lesions, including carcinomas. Thus, these transgenic mice clearly show a multistep process in hepatocarcinogenesis with remarkable synchrony and provide a promising model for analyzing the essential events of carcinogenesis at different stages.