Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program
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Elisabetta Stanzani1, Fina Martínez-Soler1,2, Teresa Martín Mateos1, Noemi Vidal3, Alberto Villanueva4,5, Miquel Angel Pujana4, Jordi Serra-Musach4, Núria de la Iglesia6, Pepita Giménez-Bonafé1 and Avelina Tortosa1,2
1 Department of Physiological Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
2 Department of Basic Nursing, Faculty of Medicine and Health Sciences, Universitat de Barcelona, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
3 Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
4 Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, IDIBELL L’Hospitalet del Llobregat, Barcelona, Spain
5 Xenopat S.L., Bellvitge Health Science Campus, L’Hospitalet del Llobregat, Barcelona, Spain
6 Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
Avelina Tortosa, email:
Fina Martínez-Soler, email:
Keywords: glioblastoma, cancer stem cells, radiotherapy, radioresistance, inflammation
Received: March 16, 2017 Accepted: May 23, 2017 Published: June 03, 2017
Glioblastoma (GBM) still remains an incurable disease being radiotherapy (RT) the mainstay treatment. Glioblastoma intra-tumoral heterogeneity and Glioblastoma-Initiating Cells (GICs) challenge the design of effective therapies. We investigated GICs and non-GICs response to RT in a paired in-vitro model and addressed molecular programs activated in GICs after RT. Established GICs heterogeneously expressed several GICs markers and displayed a mesenchymal signature. Upon fractionated RT, GICs reported higher radioresistance compared to non-GICs and showed lower α- and β-values, according to the Linear Quadratic Model interpretation of the survival curves. Moreover, a significant correlation was observed between GICs radiosensitivity and patient disease-free survival. Transcriptome analysis of GICs after acquisition of a radioresistant phenotype reported significant activation of Proneural-to-Mesenchymal transition (PMT) and pro-inflammatory pathways, being STAT3 and IL6 the major players. Our findings support a leading role of mesenchymal GICs in defining patient response to RT and provide the grounds for targeted therapies based on the blockade of inflammatory pathways to overcome GBM radioresistance.
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