Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies
| Autor: | Nicolas Demartines, Tania Santoro, Seraina Faes, Olivier Dormond, Emilie Uldry, Anne Planche, Catherine Pythoud |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Indoles Endothelium endothelium Angiogenesis sunitinib Down-Regulation Angiogenesis Inhibitors 03 medical and health sciences chemistry.chemical_compound Mice angiogenesis 0302 clinical medicine Cell Movement Medicine Animals Humans Pyrroles Protein kinase B acidity Cells Cultured Angiogenesis Inhibitors/therapeutic use Cell Proliferation/drug effects Endothelial Cells/physiology Female Hydrogen-Ion Concentration Indoles/pharmacology 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 Cell Proliferation business.industry Sunitinib Endothelial Cells Kinase insert domain receptor Vascular Endothelial Growth Factor Receptor-2 3. Good health Endothelial stem cell Vascular endothelial growth factor Vascular endothelial growth factor A 030104 developmental biology medicine.anatomical_structure Sodium Bicarbonate Oncology chemistry 030220 oncology & carcinogenesis Immunology Cancer research business medicine.drug Research Paper |
| Zdroj: | Oncotarget Oncotarget, vol. 7, no. 52, pp. 86026-86038 |
| ISSN: | 1949-2553 |
| Popis: | // Seraina Faes 1 , Emilie Uldry 1 , Anne Planche 1 , Tania Santoro 1 , Catherine Pythoud 1 , Nicolas Demartines 1 , Olivier Dormond 1 1 Department of Visceral Surgery, University Hospital of Lausanne, Switzerland Correspondence to: Olivier Dormond, email: olivier.dormond@chuv.ch Keywords: acidity, VEGF, angiogenesis, sunitinib, endothelium Received: April 22, 2016 Accepted: November 06, 2016 Published: November 12, 2016 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. |
| Databáze: | OpenAIRE |
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