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BACKGROUND AND PURPOSE: Progression of pancreatic ductal adenocarcinoma (PDAC) is promoted by desmoplasia induced by pancreatic stellate cells (PSC). Contributory to this progression is epithelial mesenchymal transition (EMT), which shares many characteristics with the cancer stem cell (CSC) hypothesis. We investigated the role of these processes on the radioresponse and tumorigenicity of pancreatic cancer cells. MATERIALS AND METHODS: We used an in vitro sphere model and in vivo xenograft model to examine the role of PSC in EMT and CSC processes. RESULTS: We demonstrated that PSC enhanced the CSC phenotype and radioresistance of pancreatic cancer cells. Furthermore, the expression of several EMT and CSC markers supported enhanced processes in our models and that translated into remarkable in vivo tumorigenicity. Multi-dose TGFβ neutralizing antibody inhibited the EMT and CSC processes, sensitized cells to radiation and reduced in vivo tumorigenicity. A proteomic screen identified multiple novel factors that were regulated by PSC in pancreatic cells. CONCLUSION: These results are critical in highlighting the role of PSC in tumor progression and radioresistance by manipulating the EMT and CSC processes. TGFβ and the novel factors identified are important targets for better therapeutic outcome in response to PSC mediated mechanisms.

Original publication

DOI

10.1016/j.radonc.2014.03.014

Type

Journal article

Journal

Radiother Oncol

Publication Date

05/2014

Volume

111

Pages

243 - 251

Keywords

Cancer stem-like cells, Epithelial mesenchymal transition, Pancreatic cancer, Pancreatic stellate cells, Radioresistance, Adenocarcinoma, Antibodies, Neutralizing, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Cell Survival, Epithelial-Mesenchymal Transition, Fibroblasts, Humans, Neoplastic Stem Cells, Pancreatic Neoplasms, Pancreatic Stellate Cells, Phenotype, Radiation Tolerance, Transforming Growth Factor beta, Tumor Cells, Cultured