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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2016; 22(31): 7046-7057
Published online Aug 21, 2016. doi: 10.3748/wjg.v22.i31.7046
Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer
Chi-Hin Wong, You-Jia Li, Yang-Chao Chen
Chi-Hin Wong, You-Jia Li, Yang-Chao Chen, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
Yang-Chao Chen, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518172, Guangdong Province, China
Author contributions: Wong CH, Li YJ and Chen YC wrote the paper.
Supported by the General Research Fund, Research Grants Council of Hong Kong, No. CUHK462211, No. CUHK462713 and No. 14102714; and the National Natural Science Foundation of China, No. 81101888 and No. 8142730.
Conflict-of-interest statement: The authors have no conflicts 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: Yang-Chao Chen, PhD, Associate Professor, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. b110796@mailserv.cuhk.edu.hk
Telephone: +852-394-31100 Fax: +852-260-35123
Received: April 9, 2016
Peer-review started: April 10, 2016
First decision: May 12, 2016
Revised: June 10, 2016
Accepted: June 28, 2016
Article in press: June 28, 2016
Published online: August 21, 2016
Processing time: 127 Days and 23 Hours
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRasG12D mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.

Keywords: Acinar cells; Acinar-to-ductal metaplasia; Pancreatic ductal adenocarcinoma; Signal transduction; Reprogramming

Core tip: Treating pancreatic ductal adenocarcinoma (PDAC) remains challenging due to the lack of effective therapeutics. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRasG12D mutation, acinar cells undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then be transformed into PanIN and eventually PDAC. This process involves MAPK, Wnt, Notch and PI3K/Akt signaling. Since ADM may be a reversible process, switching PDAC back to normal cells may also be achieved and developed as a novel therapy.