Bcl-2 delays and alters hepatic carcinogenesis induced by transforming growth factor alpha

Transgenic mice that overexpress transforming growth factor (TGF)-alpha dev elop liver tumors between 12 and 15 months of age, Tumor development is pre ceded by an overall increase in the rates of hepatocyte proliferation and c ell death. To examine the role of apoptosis in the development of TGF-alpha -induced liver tumors, we generated TGF-alpha /Bcl-2 double transgenic mic e by crossing TGF-alpha transgenic mice with Bcl-2 transgenic mice expressi ng a zinc-inducible Bcl-2 transgene. Overexpression of the Bcl-2 transgene protected hepatocytes from Fas-mediated apoptosis, We anticipated that hepa tocytes in TGF-alpha /Bcl-2 double transgenic mice would be stimulated to p roliferate but would fail to undergo apoptosis, leading to increased liver weights and accelerated tumorigenesis. At 4 weeks of age, both TGF-alpha si ngle transgenic and TGF-alpha /Bcl-2 double transgenic mice had elevated he patocyte proliferation and increased liver: body weight ratios. However, by 8 months, the liver:body weight ratios had normalized in both TGF-alpha si ngle transgenic and TGF-alpha /Bcl-2 double transgenic mice. Furthermore, B cl-2 functioned as a tumor suppressor, significantly decreasing the frequen cy and delaying the development of TGF-alpha -induced liver tumors, despite having comparable levels of TGF-alpha transgene expression in both single and double transgenic mice. Between 11 and 12 months of age, >80% of the TG F-alpha single transgenic mice had developed tumors, whereas only 54% of th e double transgenic mice had developed tumors after 13 months of age. The t umors that eventually developed in the TGF-alpha /Bcl-2 double transgenic m ice were histologically distinct and smaller in size and had lower hepatocy te mitotic activity than tumors from TGF-alpha single transgenic mice. Furt hermore, delaying Bcl-2 expression until 8.5 months of age was sufficient t o inhibit TGF-alpha -induced tumorigenesis. These results indicate that Bcl -2 inhibits tumor progression in the liver, possibly by interfering with he patocyte proliferation.