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Therapeutic Potential of Targeting Acinar Cell Reprogramming in Pancreatic Cancer

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Specialty Gastroenterology
Date 2016 Sep 10
PMID 27610015
Citations 15
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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.

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References
1.
El-Metwally T, Hussein M, Abd-El-Ghaffar S, Abo-El-Naga M, Ulrich A, Pour P . Retinoic acid can induce markers of endocrine transdifferentiation in pancreatic ductal adenocarcinoma: preliminary observations from an in vitro cell line model. J Clin Pathol. 2006; 59(6):603-10. PMC: 1860393. DOI: 10.1136/jcp.2005.032003. View

2.
Malvezzi M, Bertuccio P, Rosso T, Rota M, Levi F, La Vecchia C . European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women?. Ann Oncol. 2015; 26(4):779-786. DOI: 10.1093/annonc/mdv001. View

3.
Kobayashi Y, Uehara S, Udagawa N, Takahashi N . Regulation of bone metabolism by Wnt signals. J Biochem. 2015; 159(4):387-92. PMC: 4885935. DOI: 10.1093/jb/mvv124. View

4.
Wolpin B, OReilly E, Ko Y, Blaszkowsky L, Rarick M, Rocha-Lima C . Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. Ann Oncol. 2013; 24(7):1792-1801. PMC: 3716216. DOI: 10.1093/annonc/mdt066. View

5.
Forsdahl S, Kiselev Y, Hogseth R, Mjelle J, Mikkola I . Pax6 regulates the expression of Dkk3 in murine and human cell lines, and altered responses to Wnt signaling are shown in FlpIn-3T3 cells stably expressing either the Pax6 or the Pax6(5a) isoform. PLoS One. 2014; 9(7):e102559. PMC: 4100929. DOI: 10.1371/journal.pone.0102559. View