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Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 14, 2017; 23(14): 2470-2482
Published online Apr 14, 2017. doi: 10.3748/wjg.v23.i14.2470
Biliary tract cancer stem cells - translational options and challenges
Christian Mayr, Matthias Ocker, Markus Ritter, Martin Pichler, Daniel Neureiter, Tobias Kiesslich
Christian Mayr, Tobias Kiesslich, Department of Internal Medicine I, Paracelsus Medical University, Salzburger Landeskliniken, 5020 Salzburg, Austria
Christian Mayr, Tobias Kiesslich, Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
Matthias Ocker, Tanslational Medicine Oncology, Bayer AG, 13353 Berlin, Germany
Matthias Ocker, Department of Gastroenterology CBF, Charité University Medicine Berlin, 10117 Berlin, Germany
Markus Ritter, Laboratory for Tumour Biology and Experimental Therapies (TREAT), Laboratory for Functional and Molecular Membrane Physiology, Paracelsus Medical University, 5020 Salzburg, Austria
Markus Ritter, Department for Radon Therapy Research, Ludwig Boltzmann Cluster for Arthritis and Rehabilitation, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
Martin Pichler, Research Unit for Non-coding RNA and genome editing in cancer, Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
Daniel Neureiter, Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken, 5020 Salzburg, Austria
Daniel Neureiter, Cancer Cluster Salzburg, Salzburg 5020, Austria
Author contributions: Mayr C and Kiesslich T wrote the manuscript; Kiesslich T and Neureiter D designed tables and figure; Mayr C, Ocker M, Ritter M, Pichler M, Neureiter D and Kiesslich T equally contributed to literature research and revising the manuscript.
Supported by Studies of the authors Mayr C, Pichler M, Neureiter D and Kiesslich T in the research field of this review were supported by research grants of the Jubiläumsfonds der Österreichischen Nationalbank, No. 12677 and No. 14842; and the research fund of the Paracelsus Medical University Salzburg, No. 08/07/037, No. A-12/02/006-KIE and No. R-16/03/083-MAY.
Conflict-of-interest statement: Ocker M is an employee of Bayer AG, Berlin. Matthias Ocker owns shares of Bayer Pharma AG, Berlin. The other authors have no conflicts of interests.
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: Matthias Ocker, Professor, Tanslational Medicine Oncology, Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany. matthias.ocker@bayer.com
Telephone: +49-30-468194799
Received: January 25, 2017
Peer-review started: February 1, 2017
First decision: February 10, 2017
Revised: February 27, 2017
Accepted: March 21, 2017
Article in press: March 21, 2017
Published online: April 14, 2017
Processing time: 78 Days and 20.3 Hours
Abstract

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells - the cancer stem cells - possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

Keywords: Biliary tract cancer; cancer stem cells; Cancer stem cell markers; Tumor microenvironment; Micro-RNAs

Core tip: Using a xenograft model, researchers successfully demonstrated that as few as ten of a specific subpopulation of biliary tract cancer cells had the potency to (serially) establish and recapitulate biliary tract cancer in immunodeficient mice. Furthermore, expression of established cancer stem cell markers, cancer stem cell-related signaling pathways and micro-RNAs was reported in biliary specimens and cell lines - in most cases associated with clinical outcome. Based on these results, the existence of cancer stem cells in biliary tract is well-founded and potentially harbors new options for development of therapeutic strategies.