Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker

PLoS One. 2013 Dec 16;8(12):e80056. doi: 10.1371/journal.pone.0080056. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / metabolism*
  • Biomarkers, Tumor / metabolism*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cadherins / metabolism*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • Glioma / metabolism*
  • Glioma / pathology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Middle Aged
  • Phosphorylation
  • Tumor Microenvironment
  • Young Adult

Substances

  • Antigens, CD
  • Biomarkers, Tumor
  • Cadherins
  • cadherin 5

Grants and funding

This work was supported by the French National Institute of Health and Medical Research INSERM (UMRS 1036, U836), the French Atomic Energy and Alternative Energies Commission (CEA), Life Science division (DSV) / Institute of life sciences research and technologies (iRTSV) / Endothelial cell junctions and Angiogenesis team/ Grenoble University Hospital, Institut National du Cancer (INCa), French Association against cancer (ARC Foundation), Federation Nationale des Centres de Lutte contre le Cancer (GEFLUC Grenoble-Dauphiné-Savoie). AS and TM received grants from Courtin Arthritis Foundation. HP was a recipient of a grant from Association pour la Recherche contre le Cancer (ARC Foundation). SB and MA received grants from INCa Institut National du Cancer (INCa#:07/3D1616/PL-96-031/NG-NC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.