| First Author | Roda JM | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 6 | Pages | 3168-77 |
| PubMed ID | 22869907 | Mgi Jnum | J:333641 |
| Mgi Id | MGI:6852495 | Doi | 10.4049/jimmunol.1103817 |
| Citation | Roda JM, et al. (2012) Stabilization of HIF-2alpha induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model. J Immunol 189(6):3168-77 |
| abstractText | 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)-1alpha or HIF-2alpha, we recently demonstrated that the antitumor response to GM-CSF was dependent on HIF-2alpha-driven sVEGFR-1 production by tumor-associated macrophages, whereas HIF-1alpha specifically regulated VEGF production. We therefore hypothesized that chemical stabilization of HIF-2alpha using an inhibitor of prolyl hydroxylase domain 3 (an upstream inhibitor of HIF-2alpha 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-2alpha and increased sVEGFR-1 production from GM-CSF-treated macrophages, with no effect on HIF-1alpha 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-2alpha can therefore decrease tumor growth and angiogenesis. |
