TY - JOUR
T1 - Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma
AU - Svendsen, Agnete
AU - Verhoeff, Joost J.C.
AU - Immervoll, Heike
AU - Brøgger, Jan C.
AU - Kmiecik, Justyna
AU - Poli, Aurelie
AU - Netland, Inger A.
AU - Prestegarden, Lars
AU - Planagumà, Jesús
AU - Torsvik, Anja
AU - Kjersem, Anneli Bohne
AU - Sakariassen, Per O.
AU - Heggdal, Jan I.
AU - Van Furth, Wouter R.
AU - Bjerkvig, Rolf
AU - Lund-Johansen, Morten
AU - Enger, Per O.
AU - Felsberg, Joerg
AU - Brons, Nicolaas H.C.
AU - Tronstad, Karl J.
AU - Waha, Andreas
AU - Chekenya, Martha
N1 - Funding Information:
Acknowledgments We are grateful to the patients that consented to the use of their biopsy tissue for this research. This work was supported by The Norwegian Cancer Society (PK01-2008-0093), The Meltzer Fond, The Norwegian research Council FRIFORSK, The Bergen Medical Research Foundation, The National Genome Research Network NGFN, Brain Tumour Net (grant 01GS08187, SP8), The German Ministry for Education and Research BMBF. We thank Professor Anders Molven for STR analyses, Professor WB Stallcup and Dr L.J. Stalpers for their generosity with reagents and constructs. We thank Dr Niclou (Norlux laboratory, CRP Sante, Luxembourg) for providing us NCH421k cells used as positive controls for CD133 expression (courtesy of Dr Herold-Mende, Dept Neurosurgery, University of Heidelberg). We are very grateful to Bodil B. Hansen, Tove Johannsen, Solrun Steine, Christine Eriksen, Ingrid Strand for technical assistance and Arwed Weigel at the Molecular Imaging Center (MIC) for assistance with confocal microscopy. Proteomic and cell cycle flow cytometric analyses were performed at PROBE and MIC, respectively, University of Bergen, supported by the National Program for Research in Functional Genomics (FUGE), funded by the Norwegian Research council. Flow cytometric GBM stem cell phenotyping was conducted at Centre de Recherche de Public de la Santé, Luxembourg.
PY - 2011/10
Y1 - 2011/10
N2 - Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O 6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.
AB - Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O 6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.
KW - CD133, DNA damage
KW - Glioblastoma
KW - NG2
KW - Peroxiredoxin-1
KW - Radiation resistance
UR - http://www.scopus.com/inward/record.url?scp=84860392773&partnerID=8YFLogxK
U2 - 10.1007/s00401-011-0867-2
DO - 10.1007/s00401-011-0867-2
M3 - Article
C2 - 21863242
AN - SCOPUS:84860392773
SN - 0001-6322
VL - 122
SP - 495
EP - 510
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -