title: Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.
abstract: 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.
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Seraina
authors.initials: S
authors.lastname: Faes
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Uldry
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Planche
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Tania
authors.initials: T
authors.lastname: Santoro
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pythoud
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000494:pharmacology; D017693:Sodium Bicarbonate / Q000494:pharmacology; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D017693:Sodium Bicarbonate; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib
keywords: VEGF; acidity; angiogenesis; endothelium; sunitinib