Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program
Metrics: PDF 1516 views | HTML 2607 views | ?
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.