title: Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker.
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.
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vilgrain
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Adama
authors.initials: A
authors.lastname: Sidibé
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Helena
authors.initials: H
authors.lastname: Polena
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Francine
authors.initials: F
authors.lastname: Cand
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Mannic
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Arboleas
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Boccard
authors.affiliation: Grenoble University Hospital, Division of Internal Medicine, Grenoble, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Baudet
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gulino-Debrac
authors.affiliation: INSERM, Unit 1036, Biology of Cancer and Infection, Grenoble, France ; UJF-Grenoble 1, Biology of Cancer and Infection, Grenoble, France ; CEA, DSV/iRTSV, Biology of Cancer and Infection, Grenoble, France ; Grenoble University Hospital, Division of Internal Medicine, Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouillet
authors.affiliation: INSERM 003, Clinical Investigation Center, Grenoble University Hospital, Grenoble, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Quesada
authors.affiliation: INSERM 003, Clinical Investigation Center, Grenoble University Hospital, Grenoble, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mendoza
authors.affiliation: Grenoble University Hospital, Division of Radiology, Grenoble, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lebas
authors.affiliation: INSERM, Unit 836 Brain Nanomedicine, Grenoble Neurosciences Institut Grenoble, Grenoble, France ; Joseph Fourier University, Medicine School, Saint-Martin-d'Hères, France ; Grenoble University Hospital, Biology and Pathology Institute, Grenoble, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pelletier
authors.affiliation: INSERM, Unit 836 Brain Nanomedicine, Grenoble Neurosciences Institut Grenoble, Grenoble, France ; Joseph Fourier University, Medicine School, Saint-Martin-d'Hères, France ; Grenoble University Hospital, Division of Oncology, Grenoble, France.
authors.forename: François
authors.initials: F
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D059016:Tumor Microenvironment; D055815:Young Adult; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015820:Cadherins; D000099152:Cadherin 5