Journal
ONCOGENE
Volume 27, Issue 54, Pages 6834-6844Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.287
Keywords
glioblastoma; angiogenesis; IGFBP7; TGF-beta; Smad
Ask authors/readers for more resources
Insulin-like growth factor-binding protein 7 (IGFBP7) is a selective biomarker of glioblastoma (GBM) vessels, stronglyexpressed 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 similar to 5 pM transforming growth factor (TGF)-beta 1, a concentration sufficient to stimulate IGFBP7 in HBEC to similar levels as U87MG-CM. Both pan-TGF-beta-neutralizing antibody(1D11) and the TGF-beta 1 receptor (activin receptor-like kinase 5, ALK5) antagonist, SB431542, blocked U87MG-CM-induced IGFBP7 expression in HBEC, indicating that TGF-beta 1 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-beta 1- 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 maybe induced in brain endothelial cells by TGF-beta s secreted by GBM, most likely through TGF-beta 1/ALK5/Smad-2 pathway. Oncogene (2008) 27, 6834-6844; doi: 10.1038/onc.2008.287; published online 18 August 2008
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available