Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Inositol-requiring enzyme 1 is a key regulator of angiogenesis and invasion in malignant glioma
Gregor Aufa,b,c,1,
Arnaud Jabouillea,b,1,
Sylvaine Guérita,b,
Raphaël Pineaub,
Maylis Delugina,b,
Marion Bouchecareilha,b,d,
Noël Magnina,b,
Alexandre Favereauxb,e,
Marlène Maitref,
Timo Gaiserg,
Andreas von Deimlingg,h,
Marcus Czabankac,
Peter Vajkoczyc,
Eric Chevetb,d,
Andreas Bikfalvia,b, and
Michel Moennera,b,2
a Institut National de la Santé et de la Recherche Médicale U920, F-33400 Talence, France; b Université de Bordeaux, F-33400 Talence, France; cDepartment of Neurosurgery, Charité-Universitaetsmedizin, D-10117 Berlin, Germany; dAvenir, Institut National de la Santé et de la Recherche Médicale U889, F-33076 Bordeaux, France; ePathophysiology of Spinal Networks Group, Neurocentre Magendie, Institut National de la Santé et de la Recherche Médicale U862, F-33077 Bordeaux, France; fNeurocentre Magendie, Institut National de la Santé et de la Recherche Médicale U862, F-33077 Bordeaux, France; gDepartment of Neuropathology, University of Heidelberg, D-69120 Heidelberg, Germany; and hClinical Cooperation Unit Neuropathology, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany
Edited by Napoleone Ferrara, Genentech, Inc., South San Francisco, CA, and approved July 22, 2010 (received for review December 4, 2009)
Abstract:
Inositol-requiring enzyme 1 (IRE1) is a proximal endoplasmicreticulum (ER) stress sensor and a central mediator of the unfoldedprotein response. In a human glioma model, inhibition of IRE1 correlated with down-regulation of prevalent proangiogenicfactors such as VEGF-A, IL-1β, IL-6, and IL-8. Significantup-regulation of antiangiogenic gene transcripts was also apparent.These transcripts encode SPARC, decorin, thrombospondin-1, andother matrix proteins functionally linked to mesenchymal differentiationand glioma invasiveness. In vivo, using both the chick chorio-allantoicmembrane assay and a mouse orthotopic brain model, we observedin tumors underexpressing IRE1: (i) reduction of angiogenesisand blood perfusion, (ii) a decreased growth rate, and (iii)extensive invasiveness and blood vessel cooption. This phenotypicchange was consistently associated with increased overall survivalin glioma-implanted recipient mice. Ectopic expression of IL-6in IRE1-deficient tumors restored angiogenesis and neutralizedvessel cooption but did not reverse the mesenchymal/infiltrativecell phenotype. The ischemia-responsive IRE1 protein is thusidentified as a key regulator of tumor neovascularization andinvasiveness.
Freely available online through the PNAS open access option.
Author contributions: G.A., A.J., S.G., and M. Moenner designedresearch; G.A., A.J., S.G., R.P., M.D., M.B., M. Maitre, T.G.,and M. Moenner performed research; A.F., A.v.D., M.C., P.V.,E.C., A.B., and M. Moenner contributed new reagents/analytictools; G.A., A.J., S.G., N.M., T.G., A.v.D., M.C., P.V., A.B.,and M. Moenner analyzed data; and A.B. and M. Moenner wrotethe paper.
1G.A. and A.J. contributed equally to this work.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been depositedin the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo(accession no. GSE22385).
2To whom correspondence should be addressed. E-mail: m.moenner{at}angio.u-bordeaux1.fr.
The editors suggest the following Related Resources on Science sites:
In Science Signaling
EDITORS' CHOICE
Wei Wong (7 September 2010) Sci. Signal.3 (138), ec270.
[DOI: 10.1126/scisignal.3138ec270] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
MicroRNA-1291-mediated silencing of IRE1{alpha} enhances Glypican-3 expression.
M. Maurel, N. Dejeans, S. Taouji, E. Chevet, and C. F. Grosset (2013)
RNA
19, 778-788
|Abstract »|Full Text »|PDF »
Autocrine control of glioma cells adhesion and migration through IRE1{alpha}-mediated cleavage of SPARC mRNA.
N. Dejeans, O. Pluquet, S. Lhomond, F. Grise, M. Bouchecareilh, A. Juin, M. Meynard-Cadars, A. Bidaud-Meynard, C. Gentil, V. Moreau, et al. (2012)
J. Cell Sci.
125, 4278-4287
|Abstract »|Full Text »|PDF »
The impact of the unfolded protein response on human disease.
Differential Gene Expression in Glioblastoma Defined by ADC Histogram Analysis: Relationship to Extracellular Matrix Molecules and Survival.
W. B. Pope, L. Mirsadraei, A. Lai, A. Eskin, J. Qiao, H. J. Kim, B. Ellingson, P. L. Nghiemphu, S. Kharbanda, R. H. Soriano, et al. (2012)
AJNR Am. J. Neuroradiol.
33, 1059-1064
|Abstract »|Full Text »|PDF »
Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease.
K. Volkmann, J. L. Lucas, D. Vuga, X. Wang, D. Brumm, C. Stiles, D. Kriebel, A. Der-Sarkissian, K. Krishnan, C. Schweitzer, et al. (2011)
J. Biol. Chem.
286, 12743-12755
|Abstract »|Full Text »|PDF »
is a key regulator of angiogenesis and invasion in malignant glioma
correlated with down-regulation of prevalent proangiogenic factors such as VEGF-A, IL-1β, IL-6, and IL-8. Significant up-regulation of antiangiogenic gene transcripts was also apparent. These transcripts encode SPARC, decorin, thrombospondin-1, and other matrix proteins functionally linked to mesenchymal differentiation and glioma invasiveness. In vivo, using both the chick chorio-allantoic membrane assay and a mouse orthotopic brain model, we observed in tumors underexpressing IRE1: (i) reduction of angiogenesis and blood perfusion, (ii) a decreased growth rate, and (iii) extensive invasiveness and blood vessel cooption. This phenotypic change was consistently associated with increased overall survival in glioma-implanted recipient mice. Ectopic expression of IL-6 in IRE1-deficient tumors restored angiogenesis and neutralized vessel cooption but did not reverse the mesenchymal/infiltrative cell phenotype. The ischemia-responsive IRE1 protein is thus identified as a key regulator of tumor neovascularization and invasiveness. 
