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


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.


CONCLUSIONS
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.
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
Osama
O
Al-Assar
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
Fevzi
F
Demiciorglu
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
Serena
S
Lunardi
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
Maria Manuela
MM
Gaspar-Carvalho
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
William Gillies
WG
McKenna
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK.
Ruth M
RM
Muschel
The Radiobiology Research Institute, MRC/CR-UK Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, UK. Electronic address: thomas.brunner@uniklinik-freiburg.de.
Thomas B
TB
Brunner
D000230:Adenocarcinoma / Q000473:pathology* / Q000532:radiotherapy; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology* / Q000532:radiotherapy; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D058954:Pancreatic Stellate Cells / Q000502:physiology*; D010641:Phenotype; D011836:Radiation Tolerance / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D057134:Antibodies, Neutralizing; D014408:Biomarkers, Tumor; D016212:Transforming Growth Factor beta
Cancer stem-like cells; Epithelial mesenchymal transition; Pancreatic cancer; Pancreatic stellate cells; Radioresistance