肿瘤相关巨噬细胞生成sVEGFR-1抑制黑色素瘤生长

2012年8月13日 讯 /生物谷BIOON/ --J Immunol杂志上的一项研究证实应对缺氧环境下，巨噬细胞分泌血管内皮生长因子（VEGF）有助于肿瘤的生长和血管生成。除了血管内皮生长因子，处于低氧环境中的巨噬细胞在GM-CSF的刺激下，分泌高水平的可溶性形式的血管内皮生长因子受体（sVEGFR-1），sVEGFR-1是一种能中和血管内皮生长因子，抑制其生物活性因子。

用单核细胞/巨噬细胞选择性的去除缺氧诱导因子（HIF）-1α或HIF-2α的小鼠，我们最近表明，单核细胞/巨噬细胞在GM-CSF刺激下产生的抗肿瘤反应依赖于HIF-2α驱动肿瘤相关巨噬细胞生成sVEGFR-1，而HIF-1α调控血管内皮生长因子的生成。因此，研究人员推测使用脯氨酰羟化酶域3抑制剂（HIF-2α激活的上游抑制剂）来稳定HIF-2α的表达会增加巨噬细胞在GM-CSF刺激后sVEGFR-1的生成。

脯氨酰羟化酶域3抑制剂AKB-6899能稳定HIF-2α的表达，增加GM-CSF处理下巨噬细胞sVEGFR-1的生产，而对HIF-1α的积累或血管内皮生长因子的生成没有影响。B16F10黑色素瘤模型小鼠给予GM-CSF和AKB-6899处理后能显著降低肿瘤的生长，其抑制效果比两种药物单独治疗要好。

用GM-CSF和AKB-6899治疗的小鼠体内，检测发现sVEGFR-1 mRNA水平的增加，但血管内皮生长因子的mRNA表达未增加，同时肿瘤血管密度也减少。但小鼠用sVEGFR-1中和抗体处理后，AKB-6899的抗肿瘤功效和抗血管生成作用被抑制。这些结果表明，AKB-6899减少肿瘤的生长和血管生成是通过GM-CSF刺激肿瘤相关巨噬细胞sVEGFR-1生产的增加来实现的。（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.