Review
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Dec 14, 2008; 14(46): 7033-7058
Published online Dec 14, 2008. doi: 10.3748/wjg.14.7033
Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma
Alphonse E Sirica
Alphonse E Sirica, Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0297, United States
Author contributions: Sirica AE is the sole contributor to this work and wrote the paper.
Supported by National Institutes of Health Grants, R01 CA 83650 and R01 CA 39225 to A.E.S.
Correspondence to: Dr. Alphonse E Sirica, Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, PO Box 980297, Richmond, Virginia 23298-0297, United States. asirica@mcvh-vcu.edu
Telephone: +1-804-8289549 Fax: +1-804-8289749
Received: June 21, 2008
Revised: October 21, 2008
Accepted: October 28, 2008
Published online: December 14, 2008
Abstract

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.

Keywords: Cholangiocarcinoma; ErbB activation; Bile acids; Cyclooxygenase-2; ErbB targeted therapies