Vail M E, Pierce R H, Fausto N
Department of Pathology, University of Washington, Seattle 98195-7610, USA.
Cancer Res. 2001 Jan 15;61(2):594-601.
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 in size and had lower hepatocyte mitotic activity than tumors from TGF-alpha single transgenic mice. Furthermore, delaying Bcl-2 expression until 8.5 months of age was sufficient to inhibit TGF-alpha-induced tumorigenesis. These results indicate that Bcl-2 inhibits tumor progression in the liver, possibly by interfering with hepatocyte proliferation.
过度表达转化生长因子（TGF）-α的转基因小鼠在12至15月龄时会发生肝肿瘤。肿瘤发生之前，肝细胞增殖率和细胞死亡率总体上会增加。为了研究凋亡在TGF-α诱导的肝肿瘤发生中的作用，我们通过将TGF-α转基因小鼠与表达锌诱导型Bcl-2转基因的Bcl-2转基因小鼠杂交，培育出了TGF-α/Bcl-2双转基因小鼠。Bcl-2转基因的过度表达保护肝细胞免受Fas介导的凋亡。我们预计，TGF-α/Bcl-2双转基因小鼠的肝细胞会被刺激增殖，但不会发生凋亡，从而导致肝脏重量增加和肿瘤发生加速。4周龄时，TGF-α单转基因小鼠和TGF-α/Bcl-2双转基因小鼠的肝细胞增殖均增加，肝脏与体重之比升高。然而，到8个月时，TGF-α单转基因小鼠和TGF-α/Bcl-2双转基因小鼠的肝脏与体重之比均恢复正常。此外，尽管单转基因和双转基因小鼠中TGF-α转基因表达水平相当，但Bcl-2起到了肿瘤抑制作用，显著降低了TGF-α诱导的肝肿瘤的发生率并延迟了其发生。在11至12月龄时，超过80%的TGF-α单转基因小鼠发生了肿瘤，而双转基因小鼠在13月龄后只有54%发生了肿瘤。最终在TGF-α/Bcl-2双转基因小鼠中发生的肿瘤在组织学上有所不同，体积较小，肝细胞有丝分裂活性低于TGF-α单转基因小鼠的肿瘤。此外，将Bcl-2的表达延迟至8.5月龄足以抑制TGF-α诱导的肿瘤发生。这些结果表明，Bcl-2可能通过干扰肝细胞增殖来抑制肝脏肿瘤的进展。
