2012年8月13日 訊 /生物谷BIOON/ --J Immunol雜志上的一項研究證實應對缺氧環(huán)境下，巨噬細胞分泌血管內(nèi)皮生長因子（VEGF）有助于腫瘤的生長和血管生成,。除了血管內(nèi)皮生長因子,，處于低氧環(huán)境中的巨噬細胞在GM-CSF的刺激下，分泌高水平的可溶性形式的血管內(nèi)皮生長因子受體（sVEGFR-1）,，sVEGFR-1是一種能中和血管內(nèi)皮生長因子,，抑制其生物活性因子。
用單核細胞/巨噬細胞選擇性的去除缺氧誘導因子（HIF）-1α或HIF-2α的小鼠,，我們最近表明,，單核細胞/巨噬細胞在GM-CSF刺激下產(chǎn)生的抗腫瘤反應依賴于HIF-2α驅動腫瘤相關巨噬細胞生成sVEGFR-1，而HIF-1α調控血管內(nèi)皮生長因子的生成,。因此,，研究人員推測使用脯氨酰羥化酶域3抑制劑（HIF-2α激活的上游抑制劑）來穩(wěn)定HIF-2α的表達會增加巨噬細胞在GM-CSF刺激后sVEGFR-1的生成。
脯氨酰羥化酶域3抑制劑AKB-6899能穩(wěn)定HIF-2α的表達,，增加GM-CSF處理下巨噬細胞sVEGFR-1的生產(chǎn),，而對HIF-1α的積累或血管內(nèi)皮生長因子的生成沒有影響。B16F10黑色素瘤模型小鼠給予GM-CSF和AKB-6899處理后能顯著降低腫瘤的生長,，其抑制效果比兩種藥物單獨治療要好,。
用GM-CSF和AKB-6899治療的小鼠體內(nèi)，檢測發(fā)現(xiàn)sVEGFR-1 mRNA水平的增加,，但血管內(nèi)皮生長因子的mRNA表達未增加,，同時腫瘤血管密度也減少。但小鼠用sVEGFR-1中和抗體處理后,，AKB-6899的抗腫瘤功效和抗血管生成作用被抑制,。這些結果表明，AKB-6899減少腫瘤的生長和血管生成是通過GM-CSF刺激腫瘤相關巨噬細胞sVEGFR-1生產(chǎn)的增加來實現(xiàn)的,。（生物谷：Bioon.com）
doi:10.4049/jimmunol.1103817
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Stabilization of HIF-2alpha Induces sVEGFR-1 Production from Tumor-Associated Macrophages and Decreases Tumor Growth in a Murine Melanoma Model.
Roda, J. M., Y. Wang, et al.
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.
