Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Autor: Jesús Planagumà, Wouter R. van Furth, Jan Ingemann Heggdal, Joost J.C. Verhoeff, Per Øystein Sakariassen, Justyna Kmiecik, Agnete Svendsen, Inger Anne Netland, Martha Chekenya, Lars Prestegarden, Anneli Bohne Kjersem, Aurélie Poli, Rolf Bjerkvig, Andreas Waha, Morten Lund-Johansen, Nicolaas H. C. Brons, Karl Johan Tronstad, Per Øyvind Enger, Anja Torsvik, Heike Immervoll, Joerg Felsberg, Jan Brogger
Přispěvatelé: CCA -Cancer Center Amsterdam, Radiotherapy, ANS - Amsterdam Neuroscience, Neurosurgery, Faculteit der Geneeskunde
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Acta Neuropathologica
Acta neuropathologica, 122(4), 495-510. Springer Verlag
Acta Neuropathologica, 122(4), 495-510. Springer Verlag
ISSN: 0001-6322
Popis: 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 O6-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. Electronic supplementary material The online version of this article (doi:10.1007/s00401-011-0867-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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