Acceleron Pharma, Cambridge, MA 02139, USA.
Mol Cancer Ther. 2010 Feb;9(2):379-88. doi: 10.1158/1535-7163.MCT-09-0650. Epub 2010 Feb 2.
Activin receptor-like kinase-1 (ALK1) is a type I, endothelial cell-specific member of the transforming growth factor-beta superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-beta-related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor-, fibroblast growth factor-, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization.
激活素受体样激酶 1（ALK1）是转化生长因子-β超家族受体的一种 I 型、内皮细胞特异性成员，已知其在调节血管生成和血管维持方面发挥着重要作用。在本研究中，我们试图使用可溶性嵌合蛋白（ALK1-Fc）来研究 ALK1 信号转导抑制所介导的血管生成和肿瘤生成效应。在 29 种经表面等离子体共振筛选的转化生长因子-β相关配体中，只有骨形态发生蛋白（BMP9）和 BMP10 与 ALK1-Fc 显示出高亲和力结合。在细胞基础测定中，ALK1-Fc 抑制 BMP9 介导的人脐静脉内皮细胞中 Id-1 的表达，并抑制这些细胞在 Matrigel 基质上的脐带形成。在鸡胚绒毛尿囊膜测定中，ALK1-Fc 减少了血管内皮生长因子、成纤维细胞生长因子和 BMP10 介导的血管形成。在该测定中，ALK1-Fc 还显著抑制 B16 黑色素瘤外植体的生长。最后，ALK1-Fc 处理减少了接受 MCF7 乳腺腺癌细胞原位移植的小鼠的肿瘤负担。这些数据显示嵌合 ALK1-Fc 蛋白在减轻血管形成方面的有效性，并支持 ALK1-Fc 是一种强大的抗血管生成剂，能够阻断血管生成的观点。
