Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells

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...

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Veröffentlicht in:Radiotherapy and oncology Jg. 111; H. 2; S. 243 - 251
Hauptverfasser: Al-Assar, Osama, Demiciorglu, Fevzi, Lunardi, Serena, Gaspar-Carvalho, Maria Manuela, McKenna, William Gillies, Muschel, Ruth M., Brunner, Thomas B.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Ireland Elsevier Ireland Ltd 01.05.2014
Schlagworte:
Adenocarcinoma - pathology
Adenocarcinoma - radiotherapy
Antibodies, Neutralizing - pharmacology
Biomarkers, Tumor - analysis
Cancer stem-like cells
Carcinoma, Pancreatic Ductal - pathology
Carcinoma, Pancreatic Ductal - radiotherapy
Cell Survival - physiology
Cell Survival - radiation effects
Epithelial mesenchymal transition
Epithelial-Mesenchymal Transition - physiology
Fibroblasts - pathology
Hematology, Oncology and Palliative Medicine
Humans
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Neoplastic Stem Cells - radiation effects
Pancreatic cancer
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - radiotherapy
Pancreatic stellate cells
Pancreatic Stellate Cells - physiology
Phenotype
Radiation Tolerance - physiology
Radioresistance
Transforming Growth Factor beta - metabolism
Tumor Cells, Cultured
Radioresistance
Pancreatic stellate cells
Epithelial mesenchymal transition
Cancer stem-like cells
Pancreatic cancer
ISSN:0167-8140, 1879-0887, 1879-0887
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Zusammenfassung: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. We used an in vitro sphere model and in vivo xenograft model to examine the role of PSC in EMT and CSC processes. 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. 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0167-8140
1879-0887
1879-0887
DOI:10.1016/j.radonc.2014.03.014