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World J Gastroenterol. 2016 Aug 21;22(31):7046-57. doi: 10.3748/wjg.v22.i31.7046.

Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer.

Author information

1
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.

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 KRas(G12D) 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; Reprogramming; Signal transduction

PMID:
27610015
PMCID:
PMC4988312
DOI:
10.3748/wjg.v22.i31.7046
[Indexed for MEDLINE]
Free PMC Article

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