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Molecular and Genetic Analysis of Liver Oncogenesis in Transforming Growth Factor Transgenic Mice

Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892 [H. T., R. S., G. M.]; Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486 [C. H., T. G., M. O. B.]; and Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912 [N. F.]

Overexpression of a transforming growth factor (TGF-) transgene induced the development of liver tumors in 69 of 93 (74%) adult male mice. To identify factors associated with oncogenesis, liver tumors from transgenic animals were characterized at the molecular level. TGF- RNA transcripts were elevated in 17 of 25 (68%) liver tumors, relative to adjacent nontumorous tissue. Expression of the endogenous c-myc and insulin-like growth factor II genes was enhanced in 7 of 19 (37%) and 12 of 16 (75%) tumors, respectively. In contrast, epidermal growth factor receptor RNA levels were unchanged or reduced in all liver tumors, and mutations were not detected in either the Ha-ras or Ki-ras genes. The occurrence of liver tumors in castrated TGF- transgenic mice was reduced about 7-fold, while in ovariectomized transgenic animals the incidence was increased about 6-fold. The progeny of a cross between CD1-derived TGF- transgenic (MT42) and C57BL/6 mice exhibited no reduction in tumor burden (83%); however, the incidence of tumor formation in MT42 x FVB/N offspring was substantially lower (19%). We conclude that in these transgenic mice TGF- promotes tumor formation and appears to play a major role in tumor progression. Moreover, other factors that may collaborate in TGF--induced hepatocarcinogenesis include c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Biology, National Cancer Institute, NIH, 9000 Rockville Pike, 36/1D28, Bethesda, MD 20892.

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

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