期刊
BRITISH JOURNAL OF CANCER
卷 118, 期 9, 页码 1179-1188出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-018-0054-5
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资金
- French National Institute of Health and Medical Research INSERM [UMRS 1036]
- French Atomic Energy and Alternative Energies Commission (CEA)
- Institut de Biosciences et Biotechnologies de Grenoble (BIG)
- Grenoble University Hospital
- Institut National du Cancer [INCA 07/3D1616/PL-96-031/NG-NC]
- French Association against cancer (ARC Foundation)
- Federation Nationale des Centres de Lutte contre le Cancer (GEFLUC Grenoble-Dauphine-Savoie)
- INCA Translationnel [2016-026]
- Fondation ARC
- Fondation de France
- Fondation Mora
- ARC Foundation
- Courtin Arthritis Foundation
- Centre Leon Berard
- Centre Antoine Lacassagne
BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y-685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.
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