ALTERED GROWTH FACTOR PATHWAYS IN BILIARY CANCER

胆管癌是一种发病率和死亡率都很高的肝胆管癌，其分子发病机制尚不清楚。 此外，与肝细胞相反，对肝脏中增生性和肿瘤性胆管上皮细胞增殖是如何调节的知之甚少。 最近，我们提供的数据有力地表明，优先过度表达酪氨酸磷酸化的c-met和c-neu/erbB-2酪氨酸激酶生长因子受体代表了早期和显着的变化，在胆管癌的发病机制在呋喃大鼠模型的肝内胆管癌的发展。 我们最近还报道了免疫组化显示，与年龄匹配的正常对照肝脏中的胆管细胞相比，日本人胆管癌的肿瘤上皮细胞中c-met过表达的比例很高。 此外，我们实验室最近的原位杂交和免疫组化结果强烈表明，激活的肝细胞生长因子/c-met自分泌途径的可能性是一个标志性的变化与呋喃处理的大鼠胆管癌的发展。 基于这些发现，我们假设表皮生长因子受体家族成员和肝细胞生长途径的表达改变可能在呋喃大鼠模型和人类胆管癌的发展中起关键作用。 在目前的资助申请中提出的实验旨在将特定生长因子受体/生长因子在呋喃大鼠模型胆管癌发生中的改变与人类疾病联系起来，目的是确定它们是否也可能代表特定组织型和细胞增殖活性的人类肝胆癌发病机制中的关键和显著变化。我们还将讨论可能驱动受体基因如c-neu/erbB-2和c-met在呋喃诱导的大鼠胆管癌中过表达的特定机制，与不同种族起源和病因的人胆管癌进行比较。最后，我们将加强和扩大我们的研究，目的是证明特异性形成的肝细胞生长因子/c-met自分泌环在呋喃诱导的大鼠胆管癌细胞，并可能在某些形式的人胆管癌。 预计拟议研究产生的结果将有助于增加我们对与大鼠和人类胆管癌发展相关的重要生长因子相关改变的理解，并且也很可能为开发新的和潜在的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.