Article ; Online: Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma.
2011 Volume 122, Issue 4, Page(s) 495–510
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 ... ...
| 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. |
|||||
|---|---|---|---|---|---|---|
| MeSH term(s) | Aged ; Antigens/biosynthesis ; Antigens/genetics ; Antigens/radiation effects ; Biomarkers, Tumor/metabolism ; Biomarkers, Tumor/radiation effects ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Brain Neoplasms/radiotherapy ; DNA Damage/genetics ; DNA Damage/radiation effects ; Female ; Glioblastoma/genetics ; Glioblastoma/pathology ; Glioblastoma/radiotherapy ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Prognosis ; Proteoglycans/biosynthesis ; Proteoglycans/genetics ; Proteoglycans/radiation effects ; Radiation Tolerance ; Radiation, Ionizing ; Stem Cells/metabolism ; Stem Cells/pathology ; Stem Cells/radiation effects ; Survival Rate/trends | |||||
| Chemical Substances | Antigens ; Biomarkers, Tumor ; Proteoglycans ; chondroitin sulfate proteoglycan 4 | |||||
| Language | English | |||||
| Publishing date | 2011-08-24 | |||||
| Publishing country | Germany | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1079-0 | |||||
| ISSN | 1432-0533 ; 0001-6322 | |||||
| ISSN (online) | 1432-0533 | |||||
| ISSN | 0001-6322 | |||||
| DOI | 10.1007/s00401-011-0867-2 | |||||
| Shelf mark |
|
|||||
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Ui II Zs.188: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.