Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma.

G. Auf, A. Jabouille, S. Guerit, R. Pineau, M. Delugin, M. Bouchecareilh, N. Magnin, A. Favereaux, M. Maitre, T. Gaiser, A. von Deimling, M. Czabanka, P. Vajkoczy, E. Chevet, A. Bikfalvi, M. Moenner
Proceedings of the National Academy of Sciences. 2010-08-11; 107(35): 15553-15558
DOI: 10.1073/pnas.0914072107

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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 IRE1alpha correlated with down-regulation of
prevalent proangiogenic factors such as VEGF-A, IL-1beta, 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.


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