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Development of Liver Tumors in Transforming Growth Factor Transgenic Mice¹

Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912 [G-H. L., N. F.], and Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892 [G. M.]

We studied the development of liver tumors in male transforming growth factor (TGF-) transgenic mice of the CD1 strain and examined the expression of the transgene by immunohistochemistry and in situ hybridization. Livers of 4–5-week-old transgenic mice contained areas of centribobular hypertrophy with low glucose-6-phosphatase activity. These areas progressively expanded, and hypertrophy and dysplasia became generalized in livers of mice at 10–12 months of age. The expression of the transgene, determined by either immunohistochemistry or in situ hybridization, was uneven in animals that were 10 weeks old or older. The positive hepatocytes formed patches with a predominant centrilobular distribution. We studied a total of 23 liver tumors (7 hepatocellular carcinomas and 16 adenomas) obtained from 11 mice at 13–15 months of age and from one 7-month-old animal which received zinc sulfate to induce the transgene. The carcinomas were well differentiated tumors, without glucose-6-phosphatase or -glutamyltranspeptidase activity, that developed from the dysplastic parenchyma and occasionally within an adenoma. In all carcinomas and in 56% of the adenomas there was overexpression of the transgene in relationship to the surrounding tissue. The majority of the tumors that overexpressed TGF- were -fetoprotein positive, while -fetoprotein staining was not detected in tumors (all adenomas) that did not show excessive transgene expression. We conclude that TGF- functions as a promoter of liver carcinogenesis through its effect as an autocrine inducer of hepatocyte proliferation. Further, the data indicate that TGF- overexpression may favor tumor progression.

¹ Supported by Grant CA23226 from the National Cancer Institute.

² Present address: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706.

³ To whom requests for reprints should be addressed, at the Department of Pathology and Laboratory Medicine, Box G, Providence, RI 02912.

Received 4/ 1/92. Accepted 7/21/92.

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