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Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2017; 23(3): 382-405
Published online Jan 21, 2017. doi: 10.3748/wjg.v23.i3.382
Pancreatic stellate cell: Pandora's box for pancreatic disease biology
Ratnakar R Bynigeri, Aparna Jakkampudi, Ramaiah Jangala, Chivukula Subramanyam, Mitnala Sasikala, G Venkat Rao, D Nageshwar Reddy, Rupjyoti Talukdar
Ratnakar R Bynigeri, Aparna Jakkampudi, Ramaiah Jangala, Chivukula Subramanyam, Mitnala Sasikala, G Venkat Rao, D Nageshwar Reddy, Rupjyoti Talukdar, Institute of Basic Sciences, Asian Healthcare Foundation, Hyderabad 500082, India
D Nageshwar Reddy, Rupjyoti Talukdar, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
G Venkat Rao, Department of Surgical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
Author contributions: Bynigeri RR, Jakkampudi A and Jangala R conducted literature search, compiled references and drafted the paper; Subramanyam C, Sasikala M, Rao GV and Reddy DN contributed to manuscript drafting and provided intellectual input; Talukdar R conceived and designed the manuscript, verified content, contributed to manuscript drafting and approved the final manuscript.
Conflict-of-interest statement: The authors declare 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: Rupjyoti Talukdar, MD, Clinical Pancreatologist, Asian Institute of Gastroenterology, Clinician Scientist (Wellcome-DBT Fellow), Asian Healthcare Foundation, 6-3-661 Somajiguda, Hyderabad 500082, Telangana, India. rup_talukdar@yahoo.com
Telephone: +91-40-23378888 Fax: +91-40-23324255
Received: August 30, 2016
Peer-review started: August 31, 2016
First decision: October 10, 2016
Revised: November 9, 2016
Accepted: December 16, 2016
Article in press: December 19, 2016
Published online: January 21, 2017
Processing time: 137 Days and 8.2 Hours
Abstract

Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.

Keywords: Pancreatic stellate cells; Pancreatic fibrosis; Pancreatic cancer stroma; Physiological functions; Pancreatic stellate cells-cancer-stromal interactions; Therapeutic targets

Core tip: Pancreatic stellate cells (PSCs) have emerged as one of the major effector cells in chronic pancreatitis and pancreatic ductal adenocarcinoma. In this review, we discuss the physiological function of PSCs and the profibrogenic mechanisms. We also discuss various pathways, transcription factors and miRNAs implicated in the inflammatory and profibrogenic functions mediated by PSCs. We further discuss the crosstalk among PSCs, pancreatic cancer cells and pancreatic cancer stroma and mechanisms that lead to cancer progression, metastasis, tumour hypoxia, immune evasion and drug resistance. We conclude with recent preclinical and clinical studies that have targeted PSCs and cancer stroma.