Vessel abnormalities are among the most important features in
malignant glioma. Vascular endothelial (
VE)-cadherin is of major importance for vascular integrity. Upon
cytokine challenge,
VE-cadherin structural modifications have been described including
tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human
glioma vessels. We demonstrated that
VE-cadherin is highly expressed in human
glioma tissue and
tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon
VEGF challenge, via Src activation. In vitro experiments showed that
VEGF-induced
VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly,
metalloproteases (
MMPs) secreted by
glioma cell lines were responsible for sVE release. Because
VEGF and
MMPs are important components of tumor microenvironment, we hypothesized that
VE-cadherin proteolysis might occur in human
brain tumors. Analysis of
glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53
glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of
tumors. Altogether, these results suggest that
VE-cadherin structural modifications should be examined as candidate
biomarkers of
tumor vessel abnormalities, with promising applications in oncology.