Published online May 15, 2016. doi: 10.4291/wjgp.v7.i2.199
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
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.
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.