Hypoxia-inducible factor-2α regulates GM-CSF–derived soluble vascular endothelial growth factor receptor 1 production from macrophages and inhibits tumor growth and angiogenesis
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Macrophage secretion of vascular endothelial growth factor (VEGF) in response to the hypoxic tumor microenvironment contributes to tumor growth, angiogenesis, and metastasis. We have recently demonstrated that macrophages stimulated with GM-CSF at low O2 secrete high levels of a soluble form of the VEGF receptor 1 (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using small interfering RNA targeting to deplete hypoxia-inducible factor (HIF)-1α or HIF-2α in murine macrophages, we found that macrophage production of sVEGFR-1 in response to low O2 was dependent on HIF-2α, whereas HIF-1α specifically regulated VEGF production. In our current report, we evaluated the growth of B16F10 malignant melanoma in mice with a monocyte/macrophage-selective deletion of HIF-1α or HIF-2α (HIF-1αflox/flox- or HIF-2αflox/+/LysMcre mice). GM-CSF treatment increased intratumoral VEGF and sVEGFR-1 in control mice, an effect that was associated with a decrease in microvessel density. GM-CSF treatment of HIF-1αflox/flox/LysMcre mice induced sVEGFR-1 but not VEGF, resulting in an overall greater reduction in tumor growth and angiogenesis compared with control mice. In addition, real-time PCR for melanoma-specific genes revealed a significantly reduced presence of lung micrometastases in HIF-1αflox/flox/LysMcre mice treated with GM-CSF. Conversely, GM-CSF treatment induced VEGF but not sVEGFR-1 in HIF-2αflox/+/LysMcre mice, and, correspondingly, GM-CSF did not decrease tumor growth, angiogenesis, or lung metastasis in these mice. This study reveals opposing roles for the HIFs in the regulation of angiogenesis by tumor-associated macrophages and suggests that administration of GM-CSF might be an effective means of inducing sVEGFR-1 and inhibiting tumor growth and angiogenesis in patients with melanoma.
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The 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 [93]
The paper describes HIF-2α regulation of sVEGFR-1 production in macrophages and its effects on melanoma growth and angiogenesis (p. 3). Searches for ferroptosis, Erastin, RSL3, and therapeutic vulnerability found no passage addressing whether HIF-2α-dependent cancer cells are sensitive to ferroptosis inducers. (LLM, conf=0.75)
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 [93]
The study description (p. 3) and Discussion (p. 7) address HIF-2α in macrophage production of sVEGFR-1 and melanoma growth, not sensitivity of cancer cells to ferroptosis inducers. Searches for ferroptosis, Erastin, RSL3, ccRCC, and colon cancer found no passage addressing the attributed claim. (LLM, conf=0.76)
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- Authors
- Roda, J. M., Sumner, L. A., Evans, R., Phillips, G. S., Marsh, C. B., & Eubank, T. D.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Evans, Randall
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08
- Volume
- 187
- Issue
- 4
- Pages
- 1970-1976
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3150377
- OpenAlex
- W2147096586
- Cited by
- 74
- References
- 30
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 9 · 2013: 9 · 2012: 6
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01mh067167-03)
- National Heart, Lung, and Blood Institute (T32HL007946, R01 HL067167, T32 HL07946-06)
- National Institute of Mental Health (R01-MH067167)
- National Cancer Institute (K99CA131552, R00CA131552)
- 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
- HIF-2α, hypoxia-inducible factor-1α, soluble VEGF receptor-1, GM-CSF, tumor-associated macrophages, tumor angiogenesis, tumor growth, melanoma, vascular endothelial growth factor, tumor hypoxia, lung metastasis, microvessel density
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Lung Neoplasms, Macrophages, Melanoma, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, Oxygen, Oxygen Consumption, Gene Expression Regulation, Neoplastic, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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