ArticleOncotarget2016
Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
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- Short-Term: Cellular Metabolism and Gene Expression During the Onset of Diabetic Kidney Disease: A Diabetes Mellitus Experimental Model.International journal of molecular sciences · 2025Article
- Energy metabolism in health and diseases.Signal transduction and targeted therapy · 2025Review
- Ultrasound evaluation of peripheral intravenous catheter thrombus formation associated with intravenous flucloxacillin administration: A prospective observational pilot study.Australasian journal of ultrasound in medicine · 2025Article
- Effect of intermittent extracellular low-pH environment on human umbilical vein endothelial cell activity.PloS one · 2025Article
- Tumoroids, a valid preclinical screening platform for monitoring cancer angiogenesis.Stem cell research & therapy · 2024Review
- pH-regulated single cell migration.Pflugers Archiv : European journal of physiology · 2024Review
- Effect of acidosis on adipose-derived stem cell impairment and gene expression.Regenerative therapy · 2024Article
- Transcriptome analysis reveals molecular signature and cell-type difference of Homo sapiens endothelial-to-mesenchymal transition.G3 (Bethesda, Md.) · 2023Article
- Tissue-engineered small-diameter vascular grafts containing novel copper-doped bioactive glass biomaterials to promote angiogenic activity and endothelial regeneration.Materials today. Bio · 2023Article
- Mg-based materials diminish tumor spreading and cancer metastases.Bioactive materials · 2023Article
- Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry.Cancer metastasis reviews · 2022Review
- The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells.BMC cancer · 2022Article
- Targeting Energy Metabolism in Cancer Treatment.International journal of molecular sciences · 2022Review
- A network approach reveals driver genes associated with survival of patients with triple-negative breast cancer.iScience · 2021Article
- High-Throughput 3DFrontiers in immunology · 2021Article
- Moderately Acidic pH Promotes Angiogenesis: An In Vitro and In Vivo Study.Journal of endodontics · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.