title: Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis.
abstract: Glioblastoma (grade IV glioma/GBM) is the most common primary adult malignant brain tumor with poor prognosis. To characterize molecular determinants of tumor-stroma interaction in GBM, we profiled 48 serum cytokines and identified macrophage colony-stimulating factor (MCSF) as one of the elevated cytokines in sera from GBM patients. Both MCSF transcript and protein were up-regulated in GBM tissue samples through a spleen tyrosine kinase (SYK)-dependent activation of the PI3K-NFκB pathway. Ectopic overexpression and silencing experiments revealed that glioma-secreted MCSF has no role in autocrine functions and M2 polarization of macrophages. In contrast, silencing expression of MCSF in glioma cells prevented tube formation of human umbilical vein endothelial cells elicited by the supernatant from monocytes/microglial cells treated with conditioned medium from glioma cells. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture showed that glioma-derived MCSF induces changes in microglial secretome and identified insulin-like growth factor-binding protein 1 (IGFBP1) as one of the MCSF-regulated proteins secreted by microglia. Silencing IGFBP1 expression in microglial cells or its neutralization by an antibody reduced the ability of supernatants derived from microglial cells treated with glioma cell-conditioned medium to induce angiogenesis. In conclusion, this study shows up-regulation of MCSF in GBM via a SYK-PI3K-NFκB-dependent mechanism and identifies IGFBP1 released by microglial cells as a novel mediator of MCSF-induced angiogenesis, of potential interest for developing targeted therapy to prevent GBM progression.
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Mamatha Bangalore
authors.initials: MB
authors.lastname: Nijaguna
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Patil
authors.affiliation: the Institut de Génomique Fonctionnelle, CNRS UMR 5203, F-34094 Montpellier, France, INSERM U1191, F-34094 Montpellier, France, the Université de Montpellier, F-34094 Montpellier, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Urbach
authors.affiliation: the Departments of Neuropathology and.
authors.forename: Shivayogi D
authors.initials: SD
authors.lastname: Shwetha
authors.affiliation: the Departments of Neuropathology and.
authors.forename: Kotha
authors.initials: K
authors.lastname: Sravani
authors.affiliation: the Sri Satya Sai Institute of Higher Medical Sciences, Bangalore 560066, India.
authors.forename: Alangar S
authors.initials: AS
authors.lastname: Hegde
authors.affiliation: Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, and.
authors.forename: Bangalore A
authors.initials: BA
authors.lastname: Chandramouli
authors.affiliation: Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, and.
authors.forename: Arimappamagan
authors.initials: A
authors.lastname: Arivazhagan
authors.affiliation: the Institut de Génomique Fonctionnelle, CNRS UMR 5203, F-34094 Montpellier, France, INSERM U1191, F-34094 Montpellier, France, the Université de Montpellier, F-34094 Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.affiliation: the Departments of Neuropathology and.
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India, skumar@mcbl.iisc.ernet.in.
authors.forename: Kumaravel
authors.initials: K
authors.lastname: Somasundaram
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase
chemical_list: C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: IGFBP1; MCSF; SILAC; angiogenesis; cytokine; endothelial cell; glioblastoma; macrophage; microglia