Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor
Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor
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DOI：
10.1073/pnas.171460498
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发表时间：
2001-10-23
影响因子：
11.1
通讯作者：
Iruela-Arispe, ML
中科院分区：
文献类型：
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作者：
Rodríguez-Manzaneque, JC;Lane, TF;Iruela-Arispe, ML
肿瘤的生长和转移是已知需要新血管形成的过程。为了确定内源性血管生成抑制剂血小板反应蛋白-1（TSP 1）在肿瘤进展中的参与，我们产生了乳腺肿瘤易感小鼠，这些小鼠在乳腺中缺乏或特异性过表达TSP 1。TSP 1缺陷动物的肿瘤负荷和血管系统显著增加，肿瘤内的毛细血管出现扩张和正弦。相反，TSP 1过表达者显示肿瘤生长延迟或缺乏坦率的肿瘤发展（20%的动物）;肿瘤毛细血管显示直径减小，频率较低。有趣的是，缺乏TSP 1导致血管内皮生长因子（VEGF）与其受体VEGFR 2和更高水平的活性基质金属蛋白酶-9（MMP 9）的关联增加，MMP 9是一种先前显示促进血管生成和肿瘤侵袭的分子。在体外，MMP 9前体的酶促活化被TSP 1抑制。总之，这些结果证明了内源性血管生成抑制剂在肿瘤生长中的保护作用，并暗示了TSP 1在体内调节金属蛋白酶-9活化和VEGF信号传导。
Growth of tumors and metastasis are processes known to require neovascularization. To ascertain the participation of the endogenous angiogenic inhibitor thrombospondin-1 (TSP1) in tumor progression, we generated mammary tumor-prone mice that either lack, or specifically overexpress, TSP1 in the mammary gland. Tumor burden and vasculature were significantly increased in TSP1-deficient animals, and capillaries within the tumor appeared distended and sinusoidal. In contrast, TSP1 overexpressors showed delayed tumor growth or lacked frank tumor development (20% of animals); tumor capillaries showed reduced diameter and were less frequent. Interestingly, absence of TSP1 resulted in increased association of vascular endothelial growth factor (VEGF) with its receptor VEGFR2 and higher levels of active matrix metal-loproteinase-9 (MMP9), a molecule previously shown to facilitate both angiogenesis and tumor invasion. In vitro, enzymatic activation of proMMP9 was suppressed by TSP1. Together these results argue for a protective role of endogenous inhibitors of angiogenesis in tumor growth and implicate TSP1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling.