gms | German Medical Science

60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

Role of IRE1 in glioma development – a preclinical study

Meeting Abstract

  • G. Auf - INSERM U920, Talence, France
  • S. Guérit - INSERM U920, Talence, France
  • A. Jabouille - INSERM U920, Talence, France
  • T. Gaiser - Deutsches Krebsforschungszentrum, Heidelberg, Germany
  • A. Bikfalvi - INSERM U920, Talence, France
  • M. Moenner - INSERM U920, Talence, France

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocMI.05-03

DOI: 10.3205/09dgnc194, URN: urn:nbn:de:0183-09dgnc1947

Published: May 20, 2009

© 2009 Auf et al.
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Outline

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Objective: Ischemia is associated with glioma development and locally induces an adaptive response which confers an enhanced survival and a more agressive behaviour to tumor cells. Hypoxia or glucose deprivation activate complex intracellular signaling referred to as the Unfolded Protein Response (UPR). IRE1, one of the UPR sensors, is a key regulator of these effects. It has been previously shown that IRE1 inactivation correlated in vitro with the down-regulation of the pro-angiogenic factor VEGF-A in various tumor cell types including glioma-derived cells. The aim of this study was to further investigate the role of IRE1 in tumor development and angiogenesis.

Methods: U87 glioma cell were stably transfected either with a plasmid encoding a dominant negative IRE1 mutant (U87 IRE.DN), or with the empty vector (U87 Ctrl). Transcriptomic analysis comparing gene expression profiles of U87 Ctrl vs. U87 IRE.DN cells were performed by using an Affimetrix human gene array. For in vivo experiments, 8–10 weeks-old RAGγ mice were injected intracerebrally either with U87 Ctrl or U87 IRE.DN cells. Histopathological and immunofluorescent analysis were performed to characterize the tumor phenotypes. In vivo validation of gene expression profiles obtained in vitro and by transcriptomic analysis was performed on the chicken chorioallantoic membrane assay and in the mouse brain.

Results: Mice bearing the U87 IRE1.DN-derived tumors showed reduced tumor angiogenesis and volume, as well as an increased overall survival (>80 days) of 75% (n=15) compared to mice implanted with U87 Ctrl cells (26 days,n=14,p<0,0001). Histopathological and immunofluorescent analysis of U87 IRE1.DN tumors also revealed a major phenotypic change suggestive of a mesenchymal drift.

A functional link between the blockade of IRE1 activity and tumor vascularization was further underlined by transcriptomic analysis. The expression pattern of pro- and anti-angiogenic genes in IRE1.DN expressing cells was consistent with the inhibition of angiogenesis. Accordingly, in the CAM assay, gene expression of the potent pro-angiogenic factors VEGF-A and IL-6 was strongly decreased in U87 IRE.DN-derived tumors compared to controls (5-fold and 25-fold decrease, respectively), whereas that of the anti-angiogenic proteins such as Decorin was up-regulated (16-fold). These results were confirmed by gene expression analysis in the mouse brain.

Conclusions: Our results predict that IRE1 is a key regulator of glioma angiogenesis.