ArticleJournal of immunology (Baltimore, Md. : 1950)2012
Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model.
Article in Journal of immunology (Baltimore, Md. : 1950), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
42 citing papers in PubMed, 69 citations in OpenAlex.
- Review
- Article
- HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unraveling the role of HIF2α in melanoma progression and epithelial-mesenchymal transition.Scientific reports · 2025Article
- Comprehensive computational strategies for multi-target drug discovery in inflammatory bowel disease utilizing bioactive compounds.Scientific reports · 2025Article
- Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: from mechanisms to therapeutic opportunities.Cell communication and signaling : CCS · 2025Review
- The Regulatory Network of Transcription Factors in Macrophage Polarization.ImmunoTargets and therapy · 2025Review
- The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review.Oxygen (Basel, Switzerland) · 2023Article
- Tumour-associated macrophages: versatile players in the tumour microenvironment.Frontiers in cell and developmental biology · 2023Review
- Dynamic polarization of tumor-associated macrophages and their interaction with intratumoral T cells in an inflamed tumor microenvironment: from mechanistic insights to therapeutic opportunities.Frontiers in immunology · 2023Review
- Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.Scientific reports · 2022Article
- G-CSF/GM-CSF-induced hematopoietic dysregulation in the progression of solid tumors.FEBS open bio · 2022Review
- Revisiting the HIF switch in the tumor and its immune microenvironment.Trends in cancer · 2022Review
- Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response.Frontiers in immunology · 2022Review
- Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer.Cancers · 2021Review
- Hypoxia-dependent drivers of melanoma progression.Journal of experimental & clinical cancer research : CR · 2021Review
- Myeloid-derived suppressor cells promote epithelial ovarian cancer cell stemness by inducing the CSF2/p-STAT3 signalling pathway.The FEBS journal · 2020Article
- Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Integrated analysis of DNA methylation and mRNA expression profiles to identify key genes in head and neck squamous cell carcinoma.Bioscience reports · 2020Article
- Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal InflammationFrontiers in immunology · 2020Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Macrophage secretion of vascular endothelial growth factor (VEGF) in response to hypoxia contributes to tumor growth and angiogenesis. In addition to VEGF, hypoxic macrophages stimulated with GM-CSF secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using mice with a monocyte/macrophage-selective deletion of hypoxia-inducible factor (HIF)-1α or HIF-2α, we recently demonstrated that the antitumor response to GM-CSF was dependent on HIF-2α-driven sVEGFR-1 production by tumor-associated macrophages, whereas HIF-1α specifically regulated VEGF production. We therefore hypothesized that chemical stabilization of HIF-2α using an inhibitor of prolyl hydroxylase domain 3 (an upstream inhibitor of HIF-2α activation) would increase sVEGFR-1 production from GM-CSF-stimulated macrophages. Treatment of macrophages with the prolyl hydroxylase domain 3 inhibitor AKB-6899 stabilized HIF-2α and increased sVEGFR-1 production from GM-CSF-treated macrophages, with no effect on HIF-1α accumulation or VEGF production. Treatment of B16F10 melanoma-bearing mice with GM-CSF and AKB-6899 significantly reduced tumor growth compared with either drug alone. Increased levels of sVEGFR-1 mRNA, but not VEGF mRNA, were detected within the tumors of GM-CSF- and AKB-6899-treated mice, correlating with decreased tumor vascularity. Finally, the antitumor and antiangiogenic effects of AKB-6899 were abrogated when mice were simultaneously treated with a sVEGFR-1 neutralizing Ab. These results demonstrate that AKB-6899 decreases tumor growth and angiogenesis in response to GM-CSF by increasing sVEGFR-1 production from tumor-associated macrophages. Specific activation of HIF-2α can therefore decrease tumor growth and angiogenesis.
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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.