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Title: Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

Authors: Sherman, Mara H; Yu, Ruth T; Engle, Dannielle D; Ding, Ning; Atkins, Annette R; Tiriac, Herve; Collisson, Eric A; Connor, Frances; Van Dyke, Terry; Kozlov, Serguei; Martin, Philip; Tseng, Tiffany W; Dawson, David W; Donahue, Timothy R; Masamune, Atsushi; Shimosegawa, Tooru; Apte, Minoti V; Wilson, Jeremy S; Ng, Beverly; Lau, Sue Lynn; Gunton, Jenny E; Wahl, Geoffrey M; Hunter, Tony; Drebin, Jeffrey A; O'Dwyer, Peter J; Liddle, Christopher; Tuveson, David A; Downes, Michael; Evans, Ronald M

Published In Cell, (2014 Sep 25)

Abstract: The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

PubMed ID: 25259922 Exiting the NIEHS site

MeSH Terms: Adenocarcinoma/drug therapy*; Adenocarcinoma/pathology; Animals; Antineoplastic Agents/pharmacology*; Calcitriol/analogs & derivatives*; Calcitriol/pharmacology; Carcinoma, Pancreatic Ductal/drug therapy*; Carcinoma, Pancreatic Ductal/pathology; Cell Line, Tumor; Disease Models, Animal; Gene Expression Profiling; Humans; Mice, Inbred C57BL; Molecular Sequence Data; Pancreatic Neoplasms/drug therapy*; Pancreatic Neoplasms/pathology; Pancreatitis/drug therapy; Pancreatitis/prevention & control; Receptors, Calcitriol/metabolism*; Signal Transduction; Stromal Cells/pathology

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