Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_8C4C8F13CE80
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.
Périodique
Oncotarget
Auteur(s)
Faes S., Uldry E., Planche A., Santoro T., Pythoud C., Demartines N., Dormond O.
ISSN
1949-2553 (Electronic)
ISSN-L
1949-2553
Statut éditorial
Publié
Date de publication
27/12/2016
Peer-reviewed
Oui
Volume
7
Numéro
52
Pages
86026-86038
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments.

Mots-clé
Angiogenesis Inhibitors/therapeutic use, Animals, Cell Movement, Cell Proliferation/drug effects, Cells, Cultured, Down-Regulation, Endothelial Cells/physiology, Female, Humans, Hydrogen-Ion Concentration, Indoles/pharmacology, Mice, Mice, Inbred C57BL, Pyrroles/pharmacology, Sodium Bicarbonate/pharmacology, Vascular Endothelial Growth Factor A/pharmacology, Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2/physiology, VEGF, acidity, angiogenesis, endothelium, sunitinib
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/12/2016 18:01
Dernière modification de la notice
20/08/2019 14:50
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