TRANSGENIC HEPATOCARCINOGENESIS IN THE RAT

Although transgenic hepatocarcinogenesis has been accomplished in the mouse with a number of genetic constructs targeting the oncogene to ex pression primarily in the liver, so example of this process has yet be en developed in the rat. Because our understanding of the multistage n ature of hepatocarcinogenesis is most advanced in the rat, we have dev eloped a strain of transgenic rats carrying the promoter-enhancer sequ ences of the mouse albumin gene link;ed 5' to the simian virus-40 T an tigen gene. A line of transgenic mts bearing this transgene has been d eveloped from a single founder female. Five to six copies of the trans gene, possibly in tandem, occur within the genome of the transgenic an imals, which are maintained by heterozygous matings. Livers of transge nic animals are histologically normal after weaning; at 2 months of ag e, small foci of vacuolated cells appear in this organ, By 4 months of age, all animals exhibit focal lesions and nodules consisting primari ly of small basophilic cells, many of which exhibit considerable cytop lasmic vacuolization. Mating of animals each bearing the transgene res ults is rats with a demyelinating condition that develops acutely in p regnant females and more chronically in males. Ultrastructural studies of these cells indicate that the vacuoles contain substantial amounts of glycogen, with the cells resembling hepatoblasts. Malignant neopla sms with both a glandular and a hepatoblastoma/hepatocellular carcinom a pattern arise from the modules. Enzyme and immunohistochemical studi es of all lesions reveal many similarities in gene expression to compa rable lesions in rats subjected to chemically induced hepatocarcinogen esis, with certain exceptions. The placental form of glutathione-S-tra nsferase is absent from all lesions in the transgenic animal, as is th e expression of connexin 32. A significant number of lesions express s erum albumin, and many, but not all, exhibit the T antigen Lesions exp ressing the T antigen also contain stainable amounts of the p53 gene p roduct; by contrast, normal hepatocytes express only very low levels o f the T antigen within their nuclei and no demonstrable p53 All of the animals develop hepatic lesions, and approximately one-third also dev elop adenomas and carcinomas derived from the islet cells of the pancr eas. Although there are differences in the morphology, biology, and ge netic expression in early and late hepatic lesions in this strain of t ransgenic rat, many similarities also occur, making this a potential m odel system with which to study the interaction of environmental facto rs with a genetic program for hepatocarcinogenesis.