Sirica A E, Lai G H, Zhang Z
Department of Pathology, The Medical School at Virginia Commonwealth University, Richmond 23298-0297, USA.
J Gastroenterol Hepatol. 2001 Apr;16(4):363-72. doi: 10.1046/j.1440-1746.2001.02438.x.
Cholangiocarcinoma is a hepatic biliary cancer of high morbidity and mortality, whose molecular pathogenesis is unknown. However, there is increasing evidence to suggest that alterations in selected growth factor pathways, including an overexpression of the growth factor receptor tyrosine kinases c-ErbB-2/c-Neu and c-Met, together with possible aberrant autocrine expression of hepatocyte growth factor/scatter factor, the ligand for c-Met, may be playing important roles associated with the development of cholangiocarcinoma in both the human liver and in the furan rat model of cholangiocarcinogenesis. Cyclo-oxygenase-2, whose regulation has been experimentally related to c-ErbB-2/c-Neu as well as to hepatocyte growth factor/scatter factor, and which has been demonstrated to be overexpressed in other cancers of the gastrointestinal tract, has also been observed in preliminary studies to be upregulated in human biliary cancers and in cholangiocarcinoma induced in the furan rat model. Moreover, new data from our laboratory have demonstrated the cyclo-oxygenase-2 inhibitor NS-398 to produce a significant dose-dependent growth inhibition of rat cholangiocarcinoma cells in vitro, as well as to suppress anchorage-independent growth of these cells in soft agar. Based on the data reviewed, we propose that the selective therapeutic targeting of aberrant growth factor receptor tyrosine kinase signaling and of cyclo-oxygenase-2, alone or in combination, has potential to become a useful new approach for the treatment and/or chemoprevention of cholangiocarcinoma. We further propose that the furan rat model may serve as a powerful preclinical model for testing therapeutic and chemopreventative strategies that selectively target c-ErbB-2/c-Neu, cyclo-oxygenase-2, and/or autocrine hepatocyte growth factor/c-Met, aberrantly expressed in cholangiocarcinogenesis.
胆管癌是一种发病率和死亡率都很高的肝胆癌症，其分子发病机制尚不清楚。然而，越来越多的证据表明，某些生长因子信号通路的改变，包括生长因子受体酪氨酸激酶c-ErbB-2/c-Neu和c-Met的过表达，以及c-Met的配体肝细胞生长因子/分散因子可能存在的异常自分泌表达，在人类肝脏和胆管癌发生的呋喃大鼠模型中，可能在胆管癌的发展过程中发挥重要作用。环氧化酶-2的调控在实验上与c-ErbB-2/c-Neu以及肝细胞生长因子/分散因子相关，并且已证实在其他胃肠道癌症中过表达，在初步研究中也观察到其在人类胆管癌和呋喃大鼠模型诱导的胆管癌中上调。此外，我们实验室的新数据表明，环氧化酶-2抑制剂NS-398在体外可对大鼠胆管癌细胞产生显著的剂量依赖性生长抑制作用，并可抑制这些细胞在软琼脂中的非锚定依赖性生长。基于所综述的数据，我们提出，单独或联合选择性治疗靶向异常生长因子受体酪氨酸激酶信号传导和环氧化酶-2，有可能成为治疗和/或化学预防胆管癌的一种有用的新方法。我们进一步提出，呋喃大鼠模型可作为一种强大的临床前模型，用于测试选择性靶向在胆管癌发生过程中异常表达的c-ErbB-2/c-Neu、环氧化酶-2和/或自分泌肝细胞生长因子/c-Met的治疗和化学预防策略。
