ALTERED GROWTH FACTOR PATHWAYS IN BILLIARY CANCER

胆管细胞癌是一种发病率高、死亡率高的肝胆道癌，其分子发病机制尚不清楚。此外，与肝细胞相比，人们对肝脏中增生和肿瘤性胆管上皮细胞的增殖是如何调控的知之甚少。最近，我们提供的数据有力地表明，在呋喃大鼠肝内胆管癌变模型中，酪氨酸磷酸化的c-met和c-neu/erbB-2酪氨酸激酶生长因子受体的优先过表达代表了胆管癌发病机制的早期和显著变化。我们最近还报道了与年龄匹配的正常对照肝脏中的胆管细胞相比，日本起源的人胆管癌中相当大比例的肿瘤上皮中c-met过表达的免疫组织化学证明。此外，我们实验室最新的原位杂交和免疫组织化学结果强烈表明，激活的肝细胞生长因子/c-MET自分泌途径可能是呋喃处理的大鼠胆管癌细胞发生的标志性变化。基于这些发现，我们推测，表皮生长因子受体家族成员和肝细胞生长途径的表达变化可能在呋喃大鼠模型和人类胆管癌细胞的发展中起关键作用。目前拨款申请中提出的实验旨在将呋喃大鼠胆管癌变模型中特定的生长因子受体/生长因子变化与人类疾病联系起来，目的是确定它们是否也代表特定组织类型和细胞增殖活性的人类肝胆管癌发病机制中的关键和重大变化。我们还将探讨可能驱动c-neu/erbB-2和c-met等受体基因在呋喃诱导的大鼠胆管癌中过度表达的特定机制，并将其与不同种族来源和病因的人类胆管癌进行比较。最后，我们将加强和扩大我们的研究，旨在展示在呋喃诱导的大鼠胆管癌细胞中，可能在某些形式的人胆管癌细胞中，肝细胞生长因子/c-MET自分泌环的特定形成。预计拟议研究产生的结果将在很大程度上帮助我们加深对与大鼠和人类胆管癌细胞发展相关的重要生长因子相关变化的了解，并很可能为开发这种高度致命的癌症的新的、可能非常有效的诊断和治疗策略提供支持。

Cholangiocarcinoma is a hepatic biliary cancer of high morbidity and mortality, whose molecular pathogenesis is unknown. In addition, in contrast to hepatocytes, very little is known about how hyperplastic and neoplastic biliary epithelial cell proliferation in liver is regulated. Recently, we provided data strongly suggesting that preferential overexpression of tyrosine phosphorylated c-met and c-neu/erbB-2 tyrosine kinase growth factor receptors represent an early and significant change in cholangiocarcinoma pathogenesis in the furan rat model of intrahepatic biliary cancer development. We also recently reported on the immunohistochemical demonstration of c-met overexpression in the neoplastic epithelial of a significant percentage of human cholangiocarcinomas of Japanese origin compared with bile duct cells in age matched normal control livers. Moreover, very recent in situ hybridization and immunohistochemical results from our laboratory strongly suggest the possibility of an activated hepatocyte growth factor/c-met autocrine pathway as being a hallmark change associated with the development of cholangiocarcinoma in furan-treated rats. Based on these findings, we have hypothesized that alterations in expression of members of the epidermal growth factor family of receptors and of the hepatocyte growth pathway may play key roles in the development of cholangiocarcinoma in the furan rat model and also in the human. The experiments proposed in the current grant application are designed to link specific growth factor receptor/growth factor alterations in the furan rat model of cholangiocarcinogenesis with the human disease, with the intent of determining if they may also represent critical and significant changes in the pathogenesis of human hepatic biliary cancers of specific histiotype and cell proliferative activity. We will also address specific mechanisms that may be driving the overexpression of receptor genes like c-neu/erbB-2 and c-met in furan-induced rat cholangiocarcinomas compared with human cholangiocarcinomas of different ethnic origins and etiologies. Lastly, we will reinforce and expand our studies aimed at demonstrating specific formation of a hepatocyte growth factor/c- met autocrine loop in furan-induced rat cholangiocarcinoma cells, and possibly in some forms of human cholangiocarcinoma. It is anticipated that the results generated by the proposed research will contribute in a major way in increasing our understanding of important growth factor-linked alterations related to the development of cholangiocarcinoma in both the rat and human, and will also very likely provide the support for developing new and potentially very effective diagnostic and therapeutic strategies for this highly lethal cancer.