Editorial
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 18, 2016; 8(26): 1093-1096
Published online Sep 18, 2016. doi: 10.4254/wjh.v8.i26.1093
Cholangiocarcinoma, gone without the Wnt?
Anne T R Noll, Thorsten Cramer, Steven W M Olde Damink, Frank G Schaap
Anne T R Noll, Steven W M Olde Damink, Frank G Schaap, Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands
Thorsten Cramer, Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH Aachen University, D-52074 Aachen, Germany
Thorsten Cramer, Steven W M Olde Damink, Frank G Schaap, Euregional HPB collaboration Aachen-Maastricht, Aachen-Maastricht, Germany-The Netherlands
Author contributions: Noll ATR and Schaap FG drafted the manuscript; Cramer T and Olde Damink SWM critically reviewed the manuscript and provided important intellectual content; all authors approved the final version of the manuscript.
Conflict-of-interest statement: None of the authors has declared any conflict of interest related to this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Frank G Schaap, PhD, Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands. frank.schaap@maastrichtuniversity.nl
Telephone: +31-43-3884502
Received: January 15, 2016
Peer-review started: January 19, 2016
First decision: February 29, 2016
Revised: March 18, 2016
Accepted: August 6, 2016
Article in press: August 8, 2016
Published online: September 18, 2016
Processing time: 242 Days and 11.9 Hours
Abstract

Cholangiocarcinoma (CCA) is a relatively rare malignancy of the intra- or extra-hepatic bile ducts that is classified according to its anatomical localization as intrahepatic, perihilar or distal. Overall, CCA has a dismal prognosis due to typical presentation at an advanced irresectable stage, lack of effective non-surgical treatments, and a high rate of disease recurrence. CCA frequently arises on a background of chronic liver inflammation and cholestasis. Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells. A recent study by Boulter et al implicates the Wnt signaling cascade in cholangiocarcinogenesis. Wnt ligands Wnt7B and Wnt10A were found to be highly overexpressed in human CCA tissue. Wnt7B protein was present throughout the tumor stroma, and often co-localized with a subset of CD68+ macrophages. To address in a direct manner whether Wnt signaling is engaged in development of CCA, Boulter et al explored the Wnt signaling pathway in an experimental model that recapitulates the multi-stage progression of human CCA. Wnt ligands found to be elevated in human CCA were also upregulated during the course of CCA development following thioacetamide treatment. Wnt10a increased during the (pre-cancerous) regenerative phase, while Wnt7b induction paralleled tumor growth. Along with upregulation of target genes, the findings demonstrate that the canonical Wnt pathway is progressively activated during cholangio-carcinogenesis. Macrophage depletion, eliminating a major source of Wnt7b, prevented activation of the canonical Wnt cascade, and resulted in reduced number and volume of tumors in this model. Moreover, specific inhibitors of the canonical Wnt pathway (ICG-001 and C-59) caused reduction of tumor area and number, in xenograft and thioacetamide models of CCA. The aggregated findings show that experimental, and presumably human CCA, is a Wnt-driven tumor. Modulation of Wnt signaling, alone or in combination with surgical or chemotherapy approaches, holds promise in the management of this fatal malignancy.

Keywords: Intrahepatic cholangiocarcinoma; Liver neoplasms; Carcinogenesis; Wnt signaling pathway; Wnt7B protein; Wnt proteins

Core tip: Cholangiocarcinoma (CCA) is a relatively rare malignancy of the intra- or extra-hepatic bile ducts with dismal prognosis. CCA frequently arises on a background of chronic liver inflammation and cholestasis, which creates a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells. A recent elaborate study by Boulter et al (J Clin Invest 125:1269) has provided novel insights into the molecular pathogenesis of CCA. Involvement of the Wnt signaling pathway in cholangiocarcinogenesis, and effect of Wnt inhibitors on CCA development in vivo are discussed in this Editorial.