Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma
2010
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2010-08, Vol.107 (35), p.15553-15558
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1091-6490DOI: 10.1073/pnas.0914072107Titel-ID: cdi_proquest_miscellaneous_754005135
- Format
- –
- Schlagworte
- Animals, Brain Neoplasms - blood supply, Brain Neoplasms - metabolism, Brain Neoplasms - pathology, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane - blood supply, Chorioallantoic Membrane - metabolism, Chorioallantoic Membrane - pathology, Endoribonucleases - genetics, Endoribonucleases - metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioma - blood, Glioma - metabolism, Glioma - pathology, Humans, Immunohistochemistry, Interleukin-6 - genetics, Interleukin-6 - metabolism, Kaplan-Meier Estimate, Membrane Proteins - genetics, Membrane Proteins - metabolism, Mice, Mice, Nude, Microscopy, Fluorescence, Microscopy, Video, Neoplasm Invasiveness, Neoplasms, Experimental - blood supply, Neoplasms, Experimental - metabolism, Neoplasms, Experimental - pathology, Neovascularization, Pathologic - metabolism, Neovascularization, Pathologic - pathology, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Transplantation, Heterologous