Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma.
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.
Auf
Gregor
G
Institut National de la Santé et de la Recherche Médicale U920, F-33400 Talence, France.
Jabouille
Arnaud
A
Guérit
Sylvaine
S
Pineau
Raphaël
R
Delugin
Maylis
M
Bouchecareilh
Marion
M
Magnin
Noël
N
Favereaux
Alexandre
A
Maitre
Marlène
M
Gaiser
Timo
T
von Deimling
Andreas
A
Czabanka
Marcus
M
Vajkoczy
Peter
P
Chevet
Eric
E
Bikfalvi
Andreas
A
Moenner
Michel
M
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
D015850:Interleukin-6; D008565:Membrane Proteins; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases