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Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480698/ https://www.ncbi.nlm.nih.gov/pubmed/25924235 |
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author | Khalfaoui-Bendriss, Ghizlane Dussault, Nadège Fernandez-Sauze, Samantha Berenguer-Daizé, Caroline Sigaud, Romain Delfino, Christine Cayol, Mylène Metellus, Philippe Chinot, Olivier Mabrouk, Kamel Martin, Pierre-Marie Ouafik, L'Houcine |
author_facet | Khalfaoui-Bendriss, Ghizlane Dussault, Nadège Fernandez-Sauze, Samantha Berenguer-Daizé, Caroline Sigaud, Romain Delfino, Christine Cayol, Mylène Metellus, Philippe Chinot, Olivier Mabrouk, Kamel Martin, Pierre-Marie Ouafik, L'Houcine |
author_sort | Khalfaoui-Bendriss, Ghizlane |
collection | PubMed |
description | 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, Tyr(731), 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 Tyr(416), supporting a role of Src to phosphorylate Tyr(731)-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr(731)-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr(731)-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser(33)/Ser(37)/Thr(41) 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. |
format | Online Article Text |
id | pubmed-4480698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44806982015-06-26 Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling Khalfaoui-Bendriss, Ghizlane Dussault, Nadège Fernandez-Sauze, Samantha Berenguer-Daizé, Caroline Sigaud, Romain Delfino, Christine Cayol, Mylène Metellus, Philippe Chinot, Olivier Mabrouk, Kamel Martin, Pierre-Marie Ouafik, L'Houcine Oncotarget Research Paper 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, Tyr(731), 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 Tyr(416), supporting a role of Src to phosphorylate Tyr(731)-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr(731)-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr(731)-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser(33)/Ser(37)/Thr(41) 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. Impact Journals LLC 2015-02-05 /pmc/articles/PMC4480698/ /pubmed/25924235 Text en Copyright: © 2015 Khalfaoui-Bendriss et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Khalfaoui-Bendriss, Ghizlane Dussault, Nadège Fernandez-Sauze, Samantha Berenguer-Daizé, Caroline Sigaud, Romain Delfino, Christine Cayol, Mylène Metellus, Philippe Chinot, Olivier Mabrouk, Kamel Martin, Pierre-Marie Ouafik, L'Houcine Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title | Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title_full | Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title_fullStr | Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title_full_unstemmed | Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title_short | Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
title_sort | adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480698/ https://www.ncbi.nlm.nih.gov/pubmed/25924235 |
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