Editorial
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Mar 28, 2017; 9(9): 455-468
Published online Mar 28, 2017. doi: 10.4254/wjh.v9.i9.455
Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness
Simone Brivio, Massimiliano Cadamuro, Mario Strazzabosco, Luca Fabris
Simone Brivio, Massimiliano Cadamuro, Mario Strazzabosco, School of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy
Massimiliano Cadamuro, Mario Strazzabosco, Luca Fabris, International Center for Digestive Health, University of Milan-Bicocca, 20900 Monza, Italy
Mario Strazzabosco, Luca Fabris, Digestive Disease Section, Yale University School of Medicine, New Haven, CT 06520, United States
Luca Fabris, Department of Molecular Medicine, University of Padua School of Medicine, 35131 Padua, Italy
Author contributions: Brivio S drafted the manuscript and developed the figure; Fabris L revised any following version of manuscript and figure; Cadamuro M and Strazzabosco M contributed to editing; all authors approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
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: Luca Fabris, MD, PhD, Department of Molecular Medicine, University of Padua School of Medicine, Viale G. Colombo 3, 35131 Padua, Italy. luca.fabris@unipd.it
Telephone: +39-049-8213131 Fax: +39-049-8073310
Received: November 24, 2016
Peer-review started: November 27, 2016
First decision: January 16, 2017
Revised: January 26, 2017
Accepted: February 18, 2017
Article in press: February 20, 2017
Published online: March 28, 2017
Processing time: 119 Days and 14 Hours
Abstract

Cholangiocarcinoma (CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma (TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS (myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors (cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix (ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells (as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.

Keywords: Tumor microenvironment; Desmoplasia; Cancer-associated fibroblast; Inflammation; Tumor-associated macrophage; Lymphatic endothelial cell; Mesenchymal stem cell; Extracellular matrix

Core tip: Cholangiocarcinoma (CCA) is a typically worrisome malignancy, whose incidence has been steadily increasing. In CCA, as cancerous lesions are emerging, the surrounding stroma gradually undergoes a pathological remodeling, eventually becoming a paramount determinant of tumor growth and dissemination. Indeed, the different cell types populating the tumor microenvironment, also referred to as tumor reactive stroma, enable CCA cells to develop an aggressive phenotype, due to the secretion of a multitude of soluble factors. Therefore, functional insights into the harmful relationship between cancer and reactive stromal cells are of utmost importance, in order to unveil novel molecular targets amenable of therapeutic intervention.