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 Y685in 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.
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).
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.
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.
British journal of cancer. 2018 Mar 22 [Epub ahead of print]
Helena Polena, Julie Creuzet, Maeva Dufies, Adama Sidibé, Abir Khalil-Mgharbel, Aude Salomon, Alban Deroux, Jean-Louis Quesada, Caroline Roelants, Odile Filhol, Claude Cochet, Ellen Blanc, Céline Ferlay-Segura, Delphine Borchiellini, Jean-Marc Ferrero, Bernard Escudier, Sylvie Négrier, Gilles Pages, Isabelle Vilgrain
Univ-Grenoble Alpes, INSERM, CNRS, BIG-BCI Biology of Cancer and Infection, Grenoble, F- 38054, France., Biomedical Department, Centre Scientifique de Monaco, Monaco, Monaco., Grenoble University Hospital, Division of Internal Medicine, Grenoble, F-38043, France., INSERM, Unité 003, Clinical Investigation Center, Grenoble University Hospital, Grenoble, F-38043, France., Unicancer, Centre de Lutte contre Le Cancer Léon Bérard, Lyon, F-69008, France., Department of Clinical Research, Innovation and Statistics, Centre Antoine Lacassagne, Nice, F-06000, France., Gustave Roussy Cancer Campus, Grand Paris, Villejuif, F-94800, France., University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, F-06107, France., Univ-Grenoble Alpes, INSERM, CNRS, BIG-BCI Biology of Cancer and Infection, Grenoble, F- 38054, France. .