ALTERED GROWTH FACTOR PATHWAYS IN BILLIARY CANCER

胆道癌中生长因子途径的改变

• 批准号: 6023971
• 负责人: ALPHONSE E SIRICA
• 金额: $ 27.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6023971
• 关键词: biliary tract neoplasm; carcinoma; cell proliferation; clinical research; disease /disorder etiology; disease /disorder model; epidermal growth factor; gene expression; growth factor receptors; human subject; laboratory rat; pathologic process; protein tyrosine kinase; biliary tract neoplasm; carcinoma; cell proliferation; clinical research; disease /disorder etiology; disease /disorder model; epidermal growth factor; gene expression; growth factor receptors; human subject; laboratory rat; pathologic process; protein tyrosine kinase

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.

胆管癌是一种高发病率和死亡率的肝胆道癌，其分子发病机理尚不清楚。 此外，与肝细胞相比，对于如何调节肝脏中的增生和肿瘤胆道上皮细胞增殖，知之甚少。 最近，我们提供了强烈的数据，表明酪氨酸磷酸化的C-MET和C-NEU/ERBB-2酪氨酸激酶生长因子受体受体的优先表达代表了肝内胆管癌性癌症癌症的Furan大鼠模型中胆管癌发病机理的早期和显着变化。 我们最近还报道了C-MET过表达在肿瘤上皮中的免疫组织化学证明，与年龄相匹配的正常对照肝的胆汁导管细胞相比，日本起源的人类胆管癌很大一部分。 此外，我们实验室的最新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自分泌途径可能是与呋喃治疗的大鼠胆管癌发展有关的标志性变化。 基于这些发现，我们假设受体和肝细胞生长途径的表皮生长因子家族的表达变化可能在呋喃大鼠模型以及人类胆管癌的发展中起关键作用。 当前赠款应用中提出的实验旨在将特定生长因子受体/生长因子与人类疾病的呋喃大鼠模型中的特定生长因子/生长因子改变与人类疾病联系起来，并目的是确定它们是否也可能代表人类肝胆汁胆汁癌的特定组织型和细胞扩增活性的人类肝胆汁癌的发病机理。我们还将解决特定的机制，这些机制可能会推动与不同种族起源和病情的人类胆管癌相比，在呋喃诱导的大鼠胆管癌中，在Furan诱导的大鼠胆管癌中的受体基因过表达。最后，我们将加强和扩展我们的研究，旨在证明在呋喃诱导的大鼠胆管癌细胞中，肝细胞生长因子/c- met自分泌环的特定形成，并可能以某些形式的人胆管癌。 可以预料的是，拟议的研究产生的结果将以主要方式促进我们对与大鼠和人类胆管癌发展有关的重要生长因子互联的改变的理解，并且也很可能会为这种高度致命的癌症提供新的和潜在的非常有效的诊断和治疗策略提供支持。