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

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 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.

• Authors: Gregor Auf, Arnaud Jabouille, Sylvaine Guérit, Raphaël Pineau, Maylis Delugin, Marion Bouchecareilh, Noël Magnin, Alexandre Favereaux, Marlène Maitre, Timo Gaiser, Andreas von Deimling, Marcus Czabanka, Peter Vajkoczy, Eric Chevet, Andreas Bikfalvi, Michel Moenner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 35 Pg. 15553-8 (Aug 31 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20702765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Membrane Proteins
• ERN2 protein, human
• Protein Serine-Threonine Kinases
• Endoribonucleases

Topics

• Animals
• Brain Neoplasms (blood supply, metabolism, pathology)
• Cell Line, Tumor
• Chick Embryo
• Chorioallantoic Membrane (blood supply, metabolism, pathology)
• Endoribonucleases (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glioma (blood, metabolism, pathology)
• Humans
• Immunohistochemistry
• Interleukin-6 (genetics, metabolism)
• Kaplan-Meier Estimate
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Microscopy, Fluorescence
• Microscopy, Video
• Neoplasm Invasiveness
• Neoplasms, Experimental (blood supply, metabolism, pathology)
• Neovascularization, Pathologic (metabolism, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Transplantation, Heterologous