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PNAS 107 (35): 15553-15558

Copyright © 2010 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Inositol-requiring enzyme 1{alpha} 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 endoplasmic reticulum (ER) stress sensor and a central mediator of the unfolded protein response. In a human glioma model, inhibition of IRE1{alpha} 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.

Key Words: tumor ischemia • unfolded protein response • mesenchymal drift


Freely available online through the PNAS open access option.

Author contributions: G.A., A.J., S.G., and M. Moenner designed research; 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/analytic tools; 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 wrote the 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 deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE22385).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.0914072107/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: m.moenner{at}angio.u-bordeaux1.fr.


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