Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling

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Journal titleOncogene
Pages68346844; # of pages: 11
Subjectbio; blood supply; Brain; Capillaries; Cell Line,Tumor; Cells; Cells,Cultured; Cerebrovascular Circulation; Culture Media; Culture Media,Conditioned; cytology; drug effects; Endothelial Cells; Endothelium,Vascular; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation,Neoplastic; genetics; Glioblastoma; Human; Humans; Insulin-Like Growth Factor Binding Proteins; Neovascularization,Pathologic; pharmacology; Phosphorylation; physiology; Protein; Proteins; Rna; RNA,Messenger; secretion; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta
AbstractInsulin-like growth factor-binding protein 7 (IGFBP7) is a selective biomarker of glioblastoma (GBM) vessels, strongly expressed in tumor endothelial cells and vascular basement membrane. IGFBP7 gene regulation and its potential role in tumor angiogenesis remain unclear. Mechanisms of IGFBP7 induction and its angiogenic capacity were examined in human brain endothelial cells (HBECs) exposed to tumor-like conditions. HBEC treated with GBM cell (U87MG)-conditioned media (-CM) exhibited fourfold upregulation of IGFBP7 mRNA and protein compared to control cells. IGFBP7 gene regulation in HBEC was methylation independent. U87MG-CM analysed by enzyme-linked immunosorbent assay contained ~5 pm transforming growth factor (TGF)-β1, a concentration sufficient to stimulate IGFBP7 in HBEC to similar levels as U87MG-CM. Both pan-TGF-β-neutralizing antibody (1D11) and the TGF-β1 receptor (activin receptor-like kinase 5, ALK5) antagonist, SB431542, blocked U87MG-CM-induced IGFBP7 expression in HBEC, indicating that TGF-β1 is an important tumor-secreted effector capable of IGFBP7 induction in endothelial cells. HBEC exposed to either U87MG-CM or IGFBP7 protein exhibited increased capillary-like tube (CLT) formation in Matrigel. Both TGF-β1- and U87MG-CM-induced Smad-2 phosphorylation and U87MG-CM-induced CLT formation in HBEC were inhibited by the ALK5 antagonist, SB431542. These data suggest that proangiogenic IGFBP7 may be induced in brain endothelial cells by TGF-βs secreted by GBM, most likely through TGF-β1/ALK5/Smad-2 pathway.
Publication date
AffiliationNational Research Council Canada; NRC Institute for Biological Sciences; NRC Biotechnology Research Institute
Peer reviewedNo
NRC number52721
NPARC number9364383
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Record identifier89800e29-27b5-4751-8215-47390cc25607
Record created2009-07-10
Record modified2016-05-09
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