Hepatocarcinogenesis in transgenic mice carrying albumin-promoted SV40 T antigen gene.
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.
Department of Pathology, Cancer Institute, Tokyo.
O
O
Hino
T
T
Kitagawa
K
K
Nomura
K
K
Ohtake
L
L
Cui
Y
Y
Furuta
S
S
Aizawa
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D015152:Blotting, Northern; D003433:Crosses, Genetic; D005260:Female; D005952:Glucose-6-Phosphatase / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000382:microbiology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008940:Mitotic Index; D010957:Plasmids; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping; D012709:Serum Albumin / Q000235:genetics*; D013539:Simian virus 40 / Q000235:genetics*; D005723:gamma-Glutamyltransferase / Q000032:analysis
D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; D012709:Serum Albumin; D005723:gamma-Glutamyltransferase; D005952:Glucose-6-Phosphatase