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