Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model
Open accessAbstract
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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HIF-2α increases polyunsaturated lipids that sensitize cells to ferroptosis, an iron-dependent lipid peroxidation cell death.
“For example, HIF-2α increases levels of polyunsaturated lipids that sensitizes cells to ferroptosis, a form of necrotic cell death associated with iron-dependent lipid peroxidation [92].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [92]
The Introduction and Discussion passages describe HIF-2α-driven sVEGFR-1 production by tumor-associated macrophages and its effects on angiogenesis and tumor growth. Searches for ferroptosis, iron-dependent lipid peroxidation, and polyunsaturated lipids found no passage in our copy addressing the claimed mechanism. Page numbers were not provided. (LLM, conf=0.75)
Experimental — accuracy not yet measuredThe vulnerability of HIF-2α dependent cells to ferroptosis could be exploited therapeutically.
“Indeed, HIF-2α activation was associated with increased sensitivity to ferroptosis inducers such as Erastin and RSL3 in ccRCC and colon cancer cells suggesting that this vulnerability of HIF-2α dependent cells could be exploited for therapeutic benefit [92,93].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [92]
The Discussion describes a possible cancer therapy based on HIF-2α stabilization in macrophages and reduced tumor angiogenesis. It does not address ferroptosis or sensitivity to Erastin or RSL3 in HIF-2α-dependent cancer cells (searched: ferroptosis, Erastin, RSL3, and cell-death sensitivity). (LLM, conf=0.76)
Experimental — accuracy not yet measuredHIF-2α activation is associated with increased sensitivity to ferroptosis inducers such as Erastin and RSL3 in ccRCC and colon cancer cells.
“Indeed, HIF-2α activation was associated with increased sensitivity to ferroptosis inducers such as Erastin and RSL3 in ccRCC and colon cancer cells suggesting that this vulnerability of HIF-2α dependent cells could be exploited for therapeutic benefit [92,93].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [92]
The introduction and Discussion describe HIF-2α stabilization in tumor-associated macrophages, increased sVEGFR-1 production, and reduced angiogenesis in a murine melanoma model. Searches for ferroptosis, Erastin, RSL3, and sensitivity in renal or colon cancer cells found no passage addressing the attributed claim. (LLM, conf=0.76)
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- Authors
- Roda, J. M., Wang, Y., Sumner, L. A., Phillips, G. S., Marsh, C. B., & Eubank, T. D.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Wang, Yijie
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-09
- Volume
- 189
- Issue
- 6
- Pages
- 3168-3177
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3436995
- OpenAlex
- W2141906254
- Semantic Scholar
- b5aa16c799c1d26152a0a120cf3d8ef639e7518e
- Cited by
- 71
- References
- 49
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 8 · 2013: 7 · 2012: 1
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Akebia Therapeutics
- National Institutes of Health
- National Cancer Institute (K99CA131552, R00CA131552)
- National Center for Research Resources (KL2RR025754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- soluble fms-like tyrosine kinase-1, tumor-associated macrophages, GM-CSF, melanoma, tumor angiogenesis, hypoxia, vascular endothelial growth factor, antitumor immunity, tumor vascularity
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Antineoplastic Agents, Cells, Cultured, Disease Models, Animal, Growth Inhibitors, Humans, Macrophages, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Solubility, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, SCID, Vascular Endothelial Growth Factor Receptor-1, Cell Line, Tumor, Dioxygenases, Mice, Basic Helix-Loop-Helix Proteins, Protein Stability, Hypoxia-Inducible Factor-Proline Dioxygenases
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