Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

Abstract

Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-␤, MUC1 and MUC4, ␤-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma. (HEPATOLOGY 2005;41:5-15.)

Cyclooxygenase-2-derived Prostaglandin E2 Promotes Human Cholangiocarcinoma Cell Growth and Invasion through EP1 Receptor-mediated Activation of the Epidermal Growth Factor Receptor and Akt

“…Our data reveal that COX-2-derived PGE 2 transactivates EGFR through the EP 1 receptor in human cholangiocarcinoma cells and that this process involves the c-Src protein. Transactivation of EGFR subsequently induces Akt phosphorylation and enhances tumor cell proliferation and invasion.…”

“…Furthermore, we show that activation of EGFR by EGF increases COX-2 expression, whereas blocking PGE 2 synthesis or the EP 1 receptor attenuates EGFinduced EGFR phosphorylation, suggesting that the COX-2/ PGE 2 /EP 1 receptor pathway also modulates activation of EGFR induced by its cognate ligand. Our findings reveal a novel interaction between COX-2-derived PGE 2 and EGFR signaling that synergistically promotes cancer cell growth and invasion.…”

“…COX-2-derived PGE 2 Induces EGFR Phosphorylation in Cholangiocarcinoma Cells-Increased expression of COX-2 and EGFR in human cholangiocarcinoma cells suggests a possible interconnection between these two signaling pathways during cholangiocarcinogenesis. Given that COX-2-derived prostaglandins mediate effects primarily through specific plasma membrane receptors that are coupled with G-proteins and that certain GPCRs are known to activate EGFR (24 -26), we postulated that COX-2 may promote tumor growth through activation of EGFR.…”

“…Recent evidence suggests that cyclooxygenase-2 (COX-2) 1 -derived prostaglandin E 2 (PGE 2 ), a potent lipid inflammatory mediator, is involved in cholangiocarcinogenesis (1,2). Overexpression of COX-2 is observed in human cholangiocarcinomas and precancerous bile duct lesions (5-7); elevated COX-2 expression is also observed in an animal model of cholangiocarcinoma (8,9).…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…The tumour is much less common than HCC, but its incidence and associated mortality has been increasing steadily over the past two to three decades, with most tumours arising in persons over 50 years, suggesting that carcinogenesis is a protracted and (possibly) multi-step process [129]. Injury to the biliary epithelium with chronic inflammation, together with impedance of bile flow, are common factors in high-risk conditions for CC, such as primary sclerosing cholangitis, hepatolithiasis (gall stones) and liver fluke infestation by Opistorchis viverrini and Clonorchis sinensis.…”