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Bcl-2 Delays and Alters Hepatic Carcinogenesis Induced by Transforming Growth Factor ¹

Departments of Pathology [N. F.] and Molecular and Cellular Biology Program [M. E. V.], University of Washington, Seattle, Washington 98195-7610, and Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 [R. H. P.]

Transgenic mice that overexpress transforming growth factor (TGF)- develop liver tumors between 12 and 15 months of age. Tumor development is preceded by an overall increase in the rates of hepatocyte proliferation and cell death. To examine the role of apoptosis in the development of TGF--induced liver tumors, we generated TGF-/Bcl-2 double transgenic mice by crossing TGF- transgenic mice with Bcl-2 transgenic mice expressing a zinc-inducible Bcl-2 transgene. Overexpression of the Bcl-2 transgene protected hepatocytes from Fas-mediated apoptosis. We anticipated that hepatocytes in TGF-/Bcl-2 double transgenic mice would be stimulated to proliferate but would fail to undergo apoptosis, leading to increased liver weights and accelerated tumorigenesis. At 4 weeks of age, both TGF- single transgenic and TGF-/Bcl-2 double transgenic mice had elevated hepatocyte proliferation and increased liver:body weight ratios. However, by 8 months, the liver:body weight ratios had normalized in both TGF- single transgenic and TGF-/Bcl-2 double transgenic mice. Furthermore, Bcl-2 functioned as a tumor suppressor, significantly decreasing the frequency and delaying the development of TGF--induced liver tumors, despite having comparable levels of TGF- transgene expression in both single and double transgenic mice. Between 11 and 12 months of age, >80% of the TGF- single transgenic mice had developed tumors, whereas only 54% of the double transgenic mice had developed tumors after 13 months of age. The tumors that eventually developed in the TGF-/Bcl-2 double transgenic mice were histologically distinct and smaller in size and had lower hepatocyte mitotic activity than tumors from TGF- single transgenic mice. Furthermore, delaying Bcl-2 expression until 8.5 months of age was sufficient to inhibit TGF--induced tumorigenesis. These results indicate that Bcl-2 inhibits tumor progression in the liver, possibly by interfering with hepatocyte proliferation.

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