Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism.
Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism.
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DOI：
10.1158/0008-5472.can-08-1166
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Van Meir EG
中科院分区：
文献类型：
--
作者：
Kaur B;Cork SM;Sandberg EM;Devi NS;Zhang Z;Klenotic PA;Febbraio M;Shim H;Mao H;Tucker-Burden C;Silverstein RL;Brat DJ;Olson JJ;Van Meir EG
血管生成是肿瘤发生过程中的一个重要生理过程。关于这个过程是如何在大脑中被特别调节的，我们知之甚少。脑血管生成抑制剂-1 （BAI1）是一种主要的脑特异性七跨膜蛋白，含有5个抗血管生成血栓反应蛋白1型重复序列（TSR）。我们最近发现，BAI1在一个保守的蛋白水解裂解位点被裂解，释放出一种可溶性的、120 kDa的抗血管生成因子，称为血管抑制素（Vstat120）。Vstat120已被证明能抑制体外血管生成和皮下肿瘤生长。本文探讨其对恶性胶质瘤颅内生长的影响，并进一步探讨其抗肿瘤作用的机制。首先，我们发现Vstat120的表达强烈抑制恶性胶质瘤的颅内生长，即使存在由癌蛋白表皮生长因子受体变体III （EGFRvIII）介导的强促血管生成刺激。这种肿瘤抑制作用伴随着肿瘤血管密度的降低，表明其在大脑中具有强大的抗血管生成作用。其次，与这一解释一致的是，我们发现用Vstat120治疗可以减少体外培养的微血管内皮细胞的迁移，并抑制体内角膜血管生成。第三，我们证明了这些抗血管作用严重依赖于细胞表面受体CD36在体外和体内内皮细胞上的存在，支持Vstat120 tsr在介导这些作用中的作用。这些结果促进了对脑特异性血管生成调节的理解，并表明Vstat120在治疗脑肿瘤和其他脑血管病方面具有治疗潜力。
Angiogenesis is a critical physiological process that is appropriated during tumorigenesis. Little is known about how this process is specifically regulated in the brain. Brain Angiogenesis Inhibitor-1 (BAI1) is a primarily brain specific seven-transmembrane protein that contains five anti-angiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa anti-angiogenic factor called Vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on intracranial growth of malignant gliomas and further study the mechanism of its anti-tumor effects. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong pro-angiogenic stimulus mediated by the oncoprotein Epidermal Growth Factor Receptor variant III (EGFRvIII). This tumor suppressive effect is accompanied by a decrease in vascular density in the tumors, suggesting a potent anti-angiogenic effect in the brain. Second, and consistent with this interpretation, we find that treatment with Vstat120 reduces the migration of cultured microvascular endothelial cells in vitro and inhibits corneal angiogenesis in vivo. Third, we demonstrate that these anti-vascular effects are critically dependent on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting a role of the Vstat120 TSRs in mediating these effects. These results advance the understanding of brain-specific angiogenic regulation, and suggest that Vstat120 has therapeutic potential in the treatment of brain tumors and other intra-cerebral vasculopathies.