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

Agnete Svendsen, Joost J.C. Verhoeff, Heike Immervoll, Jan C. Brøgger, Justyna Kmiecik, Aurelie Poli, Inger A. Netland, Lars Prestegarden, Jesús Planagumà, Anja Torsvik, Anneli Bohne Kjersem, Per O. Sakariassen, Jan I. Heggdal, Wouter R. Van Furth, Rolf Bjerkvig, Morten Lund-Johansen, Per O. Enger, Joerg Felsberg, Nicolaas H.C. Brons, Karl J. TronstadAndreas Waha, Martha Chekenya*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

96 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)495-510
Number of pages16
JournalActa Neuropathologica
Volume122
Issue number4
DOIs
Publication statusPublished - Oct 2011

Keywords

  • CD133, DNA damage
  • Glioblastoma
  • NG2
  • Peroxiredoxin-1
  • Radiation resistance

Fingerprint

Dive into the research topics of 'Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma'. Together they form a unique fingerprint.

Cite this