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Reactivation of Insulin-like Growth Factor II during Hepatocarcinogenesis in Transgenic Mice Suggests a Role in Malignant Growth¹

Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 [P. S., D. Y., C. E. R.]; Roswell Park Cancer Center, Buffalo, New York 14263 [W. A. H., Y. R.]; and Scripps Clinic and Research Foundation, La Jolla, California 92037 [F. V. C.]

We have studied the expression of insulin-like growth factor II (IGF-II) during hepatocarcinogenesis in four independent transgenic mouse lines. In all four lines liver-directed transgene expression induces a stepwise and relatively synchronized tumorigenesis. IGF-II reexpression occurs in all four lines irrespective of the mechanism of tumor induction. Reexpression is chronologically associated with late progression steps toward hepatocellular carcinoma and correlated with the respective tumor progression rate in each line. IGF-II activation is focal and topographically associated with high replicative activity. IGF-II mRNAs in hepatocellular carcinomas show similarities to the expression pattern in fetal liver, and a M_r 15,000 IGF-II polypeptide accumulates intracellularly in distinct cytoplasmic preferentially perinuclear compartments. These data indicate that IGF-II reexpression is a marker for progression to hepatocellular carcinoma and may contribute to hepatocarcinogenesis via an autocrine mechanism.

¹ P. S. was sponsored by Research Fellowship Schi 273/2-1 of the Deutsche Forschungsgemeinschaft. This work was supported by Institutional Research Grant IN-54-29 of the American Cancer Society, grants from the Buffalo Foundation and the Association for Research of Childhood Cancer, National Cancer Institute Grant CA50675 (W. A. H.), USPHS Grant CA37232 from the National Cancer Institute, Grant DK-17702 from the Digestive Disease Center Grant Program, Grant 2P30 CA1333020 from the Cancer Center Core Grant Program, and Grant FRA-316 from the American Cancer Society (C. E. R.).

² Present address: Institute of Pathology, University Hospital, Langenbeckstr. 1, 6500 Mainz, Germany.

³ To whom requests for reprints should be addressed, at Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park, Bronx, NY 10461.

Received 9/26/91. Accepted 2/21/92.

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