Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling
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Ghizlane Khalfaoui-Bendriss1,2,*, Nadège Dussault1,2,*, Samantha Fernandez-Sauze1,2, Caroline Berenguer-Daizé1,2, Romain Sigaud1,2, Christine Delfino1,2, Mylène Cayol1,2, Philippe Metellus1,2, Olivier Chinot1,2, Kamel Mabrouk3, Pierre-Marie Martin1,2,4, L’Houcine Ouafik1,2,4
1Aix Marseille Université, CRO2, UMR_S 911, Faculté de Médecine, Marseille, France
2Inserm, U911-CRO2, Marseille, France
3Aix-Marseille Université, CNRS, UMR 7273, Institut de Chimie Radicalaire (ICR) Marseille, France
4AP-HM, CHU Nord, Service de Transfert d’Oncologie Biologique, Marseille, France
*These authors have contributed equally to this work
L’Houcine Ouafik, e-mail: email@example.com
Keywords: adrenomedullin, tumor neovessels, angiogenesis, VE-cadherin, β-catenin
Received: November 27, 2014 Accepted: January 19, 2015 Published: February 05, 2015
The cellular and molecular mechanisms by which adrenomedullin (AM) blockade suppresses tumor neovessels are not well defined. Herein, we show that AM blockade using anti-AM and anti-AM receptors antibodies targets vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and induces regression of unstable nascent tumor neovessels. The underlying mechanism involved, and shown in vitro and in vivo in mice, is the disruption of the molecular engagement of the endothelial cell-specific junctional molecules vascular endothelial-cadherin (VE-cadherin)/β-catenin complex. AM blockade increases endothelial cell permeability by inhibiting cell-cell contacts predominantly through disruption of VE-cadherin/β-catenin/Akt signalling pathway, thereby leading to vascular collapse and regression of tumor neovessels. At a molecular level, we show that AM blockade induces tyrosine phosphorylation of VE-cadherin at a critical tyrosine, Tyr731, which is sufficient to prevent the binding of β-catenin to the cytoplasmic tail of VE-cadherin leading to the inhibition of cell barrier function. Furthermore, we demonstrate activation of Src kinase by phosphorylation on Tyr416, supporting a role of Src to phosphorylate Tyr731-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr731-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr731-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser33/Ser37/Thr41 sites in both ECs and VSMCs both in vitro and in vivo in mice. These data suggest that AM blockade selectively induces regression of unstable tumor neovessels, through disruption of VE-cadherin signalling. Targeting AM system may present a novel therapeutic target to selectively disrupt assembly and induce regression of nascent tumor neovessels, without affecting normal stabilized vasculature.
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