Oncogene-induced liver neoplasia in transgenic mice.
Models of hepatocarcinogenesis were generated by directing the expression of SV40 T-antigens, an oncogenic mutant of c-H-ras, or c-myc to the liver of transgenic mice using the albumin enhancer/promoter. The majority of mice carrying the ras transgene (group A) were born with enlarged livers and atypical hepatic architecture, and these all died within several days of birth. The remaining ras transgenic mice (group B) had lower levels of hepatic ras expression, exhibited mild hepatic dysplasia but no liver enlargement, and all ultimately died from development of lung tumors. In contrast, the livers of mice expressing T-antigens were relatively normal at birth, by one month displayed marked dysplasia, and by three to seven months developed multiple nodular adenomas and carcinomas. Myc expression caused mild to severe hepatic dysplasia in young mice, and focal hepatic adenomas in some mice over fifteen months of age. Lines of mice expressing ras (group B), T-antigen, or myc were established and crossed with each other to generate dual transgenic mice expressing oncogene pairs. Each combination resulted in accelerated tumor development, suggesting that these oncoproteins can cooperate with one another during multistep hepatic transformation.
Sandgren
E P
EP
Laboratory of Reproductive Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104.
Quaife
C J
CJ
Pinkert
C A
CA
Palmiter
R D
RD
Brinster
R L
RL
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D012709:Serum Albumin / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics
D000957:Antigens, Viral, Tumor; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012709:Serum Albumin; D016283:Proto-Oncogene Proteins p21(ras)