Matrix Metalloproteinase-14 (MT1-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis
Matrix Metalloproteinase-14 (MT1-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis
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DOI：
10.1158/0008-5472.can-09-4466
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
ten Dijke, Peter
中科院分区：
文献类型：
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作者：
Hawinkels, Lukas J. A. C.;Kuiper, Patricia;ten Dijke, Peter
内皮糖蛋白是一种转化生长因子-β辅助受体，在血管生成中起关键作用。内皮糖蛋白的可溶性形式存在于循环中，但可溶性内皮糖蛋白（sEndoglin）的作用知之甚少。此外，内皮糖蛋白脱落机制尚不清楚。因此，我们研究了sEndoglin在肿瘤血管生成中的作用以及endoglin的细胞外结构域从膜释放的机制。在结直肠癌标本中，与健康对照组相比，我们观察到高内皮内皮糖蛋白表达，伴随着循环中sEndoglin水平略低。使用内皮发芽测定的体外分析显示，sEndoglin减少自发和血管内皮生长因子诱导的内皮发芽。发现人脐血管内皮细胞分泌高水平的sEndoglin。基质金属蛋白酶（MMP）抑制剂和MMP-14短发夹RNA抑制Endoglin脱落，表明MMP-14是主要的endoglin脱落蛋白酶。endoglin和膜结合MMP-14的共表达导致sEndoglin水平的强烈增加。内皮糖蛋白脱落需要内皮糖蛋白和膜定位的MMP-14之间的直接相互作用。使用切割位点突变体，我们确定MMP-14切割endoglin在一个网站在靠近跨膜结构域。总之，这项研究表明，MMP-14介导内皮糖蛋白脱落，这可能会调节（结直肠）肿瘤微环境中的内皮细胞的血管生成潜力。Cancer Res; 70（10）; 4141-50. (C)2010年AACR。
Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane. In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment. Cancer Res; 70(10); 4141-50. (C) 2010 AACR.