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

Mary Eliabeth Vail, Robert H Pierce, Nelson Fausto

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Abstract

Transgenic mice that overexpress transforming growth factor (TGF)-alpha 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-alpha-induced liver tumors, we generated TGF-alpha/Bcl-2 double transgenic mice by crossing TGF-alpha 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-alpha/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-alpha single transgenic and TGF-alpha/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-alpha single transgenic and TGF-alpha/Bcl-2 double transgenic mice. Furthermore, Bcl-2 functioned as a tumor suppressor, significantly decreasing the frequency 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 TGF-alpha 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-alpha/Bcl-2 double transgenic mice were histologically distinct and smaller
Original languageEnglish
Pages (from-to)594 - 601
Number of pages8
JournalCancer Research
Volume61
Issue number2
Publication statusPublished - 2001

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