The Molecular Pathogenesis of Cholangiocarcinoma

Berthiaume, Eric; Wands, Jack R.

doi:10.1055/s-2004-828890

Cited by 94 publications

(58 citation statements)

References 55 publications

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“…Given that the G s -coupled EP 2 and EP 4 receptors mediate their effect via increasing intracellular cAMP levels and that activation of cAMP/protein kinase A signaling is known to enhance the proliferation and motility of cholangiocytes and cholangiocarcinoma cells, the lack of EP 2 and EP 4 receptor effect revealed in this study further underscores the importance of EP 1 receptormediated EGFR transactivation in cholangiocarcinoma progression. It is of further interest that the experiments with the EP 3 receptor agonist ONO-AE-248 and EP 3 receptor siRNA also failed to show involvement of the G i -coupled EP 3 receptor, despite that fact that G i is known to exert its effect through reduction of cAMP.…”

Section: Discussionmentioning

confidence: 99%

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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

Han

2005

Journal of Biological Chemistry

128

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Cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis has recently been implicated in human cholangiocarcinogenesis. This study was designed to examine the mechanisms by which COX-2-derived prostaglandin E 2 (PGE 2 ) regulates cholangiocarcinoma cell growth and invasion. Immunohistochemical analysis revealed elevated expression of COX-2 and the epidermal growth factor (EGF) receptor (EGFR) in human cholangiocarcinoma tissues. Overexpression of COX-2 in a human cholangiocarcinoma cell line (CCLP1) increased tumor cell growth and invasion in vitro and in severe combined immunodeficient mice. Overexpression of COX-2 or treatment with PGE 2 or the EP 1 receptor agonist ONO-DI-004 induced phosphorylation of EGFR and enhanced tumor cell proliferation and invasion, which were inhibited by the EP 1 receptor small interfering RNA or antagonist ONO-8711. Treatment of CCLP1 cells with PGE 2 or ONO-DI-004 enhanced binding of EGFR to the EP 1 receptor and c-Src. Furthermore, PGE 2 or ONO-DI-004 treatment also increased Akt phosphorylation, which was blocked by the EGFR tyrosine kinase inhibitors AG 1478 and PD 153035. These findings reveal that the EP 1 receptor transactivated EGFR, thus activating Akt. On the other hand, activation of EGFR by its cognate ligand (EGF) increased COX-2 expression and PGE 2 production, whereas blocking PGE 2 synthesis or the EP 1 receptor inhibited EGF-induced EGFR phosphorylation. This study reveals a novel cross-talk between the EP 1 receptor and EGFR signaling that synergistically promotes cancer cell growth and invasion.

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Section: Discussionmentioning

confidence: 99%

“…The most abundant prostaglandin in cholangiocarcinoma cells is PGE 2 (15). There are four EP receptor subtypes that can bind to PGE 2 : EP 1 , EP 2 , EP 3 , and EP 4 . The EP 1 receptor is coupled with the G q protein and thus signals through phospholipase C and intracellular Ca 2ϩ .…”

mentioning

confidence: 99%

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

Han

2005

Journal of Biological Chemistry

128

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“…10 In fact, many mutations in oncogenes and tumor suppressor genes have been identified in human CC tissues, suggest- ing that biliary neoplastic cells may arise from cellular and consequent DNA injury. 22 However, how somatic mutations accumulate through the process of human cholangiocarcinogenesis is unknown. In the current study, we demonstrated that a recently identified DNA editing enzyme, AID, is induced by proinflammatory cytokine stimulation in biliary epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

et al. 2008

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Chronic inflammation plays a critical role in oncogenesis in various human organs. Epidemiological studies have demonstrated that patients with primary sclerosing cholangitis have a predisposition to develop cholangiocarcinoma (CC). However, the molecular mechanisms that account for the development of bile duct carcinomas are not well defined. We recently provided evidence that activation-induced cytidine deaminase (AID), a member of the DNA/ RNA editing enzyme family, is implicated in human tumorigenesis via its mutagenic activity. We found here that ectopic AID production is induced in response to tumor necrosis factor-␣ ( C holangiocarcinoma (CC) is an epithelial neoplasm that originates from the bile duct and can occur at any level of the biliary tree. 1,2 The incidence CC is increasing worldwide; it is the second most common primary hepatobiliary malignancy. 2 Although most CC arise in the absence of apparent risk factors, chronic inflammation of the biliary epithelium plays a critical role for their development. 2 In fact, primary sclerosing cholangitis (PSC) is the commonest predisposing condition for cholangiocarcinogenesis, and the prevalence of CC in patients with PSC ranges from 9% to 23%, with a cumulative annual risk of 1.5% per year of the disease. 1 Other risk factors for cholangiocarcinogenesis are also associated with chronic biliary tract inflammation, including chronic choledocholithiasis, liver fluke infestation, hepatolithiasis, Caroli's disease, and hepatitis C viral infection. 1 It has been hypothesized that the increased risk of CC in these conditions occurs because of chronic epithelial inflammation leading to cell proliferation, along with enhanced production of endogenous mutagens in the bile. 1 However, the precise molecular mechanism that accounts for the development of CC on the basis of chronic biliary tract inflammation remains unsolved.

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“…It is beyond the scope of this review to provide a detailed analysis of each of these factors and their relationship to the molecular pathogenesis of cholangiocarcinoma. However, the reader is referred to the several recent reviews 7,[42][43][44][45][46][47] for an updated analysis of the molecular pathological features of cholangiocarcinoma. This section instead highlights such factors as tumor location, subtype, and grade, which have been found to be associated with variations in the frequencies of expression of selected molecular alterations and which need to be considered when assessing outcome and in devising molecular therapeutic strategies for cholangiocarcinoma.…”

Section: Molecular Alterations and Variationsmentioning

confidence: 99%

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

2005

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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.)

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The Molecular Pathogenesis of Cholangiocarcinoma

Cited by 94 publications

References 55 publications

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

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

Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

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