Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 35, Pages 15553-15558Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914072107
Keywords
tumor ischemia; unfolded protein response; mesenchymal drift
Categories
Funding
- Ministere de l'Education Nationale de l'Enseignement Superieur et de la Recherche
- Institut National de la Sante et de la Recherche Medicale
- Ligue Nationale Contre le Cancer, Comite de la Gironde
- Association pour la Recherche sur le Cancer [3694, 1097]
- Institut National du Cancer
- Fondation pour la Recherche Medicale
- European Consortium for Tumor Angiogenesis Research
- [IFR66]
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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 IRE1 alpha correlated with down-regulation of prevalent proangiogenic factors such as VEGF-A, IL-1 beta, 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 under-expressing 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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