Sirica Alphonse-E
Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0297, USA.
World J Gastroenterol. 2008 Dec 14;14(46):7033-58. doi: 10.3748/wjg.14.7033.
Aberrant expression and signaling of epidermal growth factor receptor (ErbB) family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbB-directed therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2, interleukin-6/gp130, transmembrane mucins, hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.
表皮生长因子受体（ErbB）家族受体酪氨酸激酶的异常表达和信号传导，尤其是ErbB2和ErbB1，与肝内胆管癌的分子发病机制有关。恶性胆管细胞中ErbB2和/或ErbB1的组成性过表达引发了人们对以下可能性的兴趣：选择性靶向这些受体的药物可能对胆管癌治疗有效。然而，目前这类针对ErbB的治疗方法在胆管癌患者中最多只能产生适度的反应。本综述对临床前和临床研究进行了全面且批判性的分析，旨在评估ErbB2和/或ErbB1表达改变、基因修饰以及信号传导失调在胆管癌发生和发展中的作用。讨论了用于评估人胆管癌标本中ErbB2和/或ErbB1过表达及基因扩增的实验方法的具体局限性。此外，还综述了目前与组成性ErbB2过表达相关的肝内胆管癌发生的啮齿动物模型。还详细阐述了ErbB2或ErbB1与其他与肝内胆管癌发生和发展相关的分子信号通路之间的特定相互作用关系，包括那些将ErbB受体与胆汁酸、环氧化酶-2、白细胞介素-6/gp130、跨膜粘蛋白、肝细胞生长因子/Met以及血管内皮生长因子信号传导联系起来的关系。最后，考虑了可能限制针对胆管癌的ErbB靶向药物治疗效果的各种因素。
