title: Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model.
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.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Roda
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.forename: Laura A
authors.initials: LA
authors.lastname: Sumner
authors.forename: Gary S
authors.initials: GS
authors.lastname: Phillips
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Eubank
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D049308:Dioxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D055550:Protein Stability; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D049308:Dioxygenases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006131:Growth Inhibitors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C488894:EGLN3 protein, human