Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. May 15, 2016; 7(2): 199-210
Published online May 15, 2016. doi: 10.4291/wjgp.v7.i2.199
Differential role of Hedgehog signaling in human pancreatic (patho-) physiology: An up to date review
Eckhard Klieser, Stefan Swierczynski, Christian Mayr, Tarkan Jäger, Johanna Schmidt, Daniel Neureiter, Tobias Kiesslich, Romana Illig
Eckhard Klieser, Johanna Schmidt, Daniel Neureiter, Romana Illig, Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Stefan Swierczynski, Tarkan Jäger, Department of Surgery, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Christian Mayr, Tobias Kiesslich, Department of Internal Medicine I, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Christian Mayr, Tobias Kiesslich, Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
Author contributions: Mayr C and Kiesslich T designed the figures; Neureiter D and Illig R outlined and designed the manuscript; all authors contributed individual chapters of the manuscript.
Conflict-of-interest statement: The authors declared no conflict of interest.
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: Daniel Neureiter, MA, Associate Professor, Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Müllner Haupstrasse 48, 5020 Salzburg, Austria. d.neureiter@salk.at
Telephone: +43-662-44824701
Received: July 27, 2015
Peer-review started: July 30, 2015
First decision: September 28, 2015
Revised: October 21, 2015
Accepted: March 7, 2016
Article in press: March 9, 2016
Published online: May 15, 2016
Abstract

Since the discovery of the Hedgehog (Hh) pathway in drosophila melanogaster, our knowledge of the role of Hh in embryonic development, inflammation, and cancerogenesis in humans has dramatically increased over the last decades. This is the case especially concerning the pancreas, however, real therapeutic breakthroughs are missing until now. In general, Hh signaling is essential for pancreatic organogenesis, development, and tissue maturation. In the case of acute pancreatitis, Hh has a protective role, whereas in chronic pancreatitis, Hh interacts with pancreatic stellate cells, leading to destructive parenchym fibrosis and atrophy, as well as to irregular tissue remodeling with potency of initiating cancerogenesis. In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment. The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials (phases 1 and 2). Furthermore, a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach. In this review, we give a structured survey of the role of the Hh pathway in pancreatic development, pancreatitis, pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

Keywords: Pancreatic cancer, Hedgehog, Pancreatitis, Pancreas, Development

Core tip: The Hedgehog (Hh) pathway is a ligand-dependent and evolutionary conserved cellular signaling mechanism with various physiologic (development) and pathogenetic functions (especially carcinogenesis). Concerted Hh signaling is essential for human pancreatic development and homeostasis of the gastrointestinal tract. Aberrant expression within the Hh signaling pathway results in malformations like annular pancreas. The Janus aspect of Hh in pancreatitis is reflected by the protective role of Hh in acute pancreatitis vs the disease-progressive function of Hh in chronic pancreatitis (CP), whereby CP is linked to pancreatic cancerogenesis via pancreatic intraepithelial neoplasia (PanIn). Starting with PanIn and ending up at metastatic disease, Hh pathway is expressed in ductal pancreatic cancer thereby influencing and being paracrine influenced by the tumor microenvironment.