Disruption of matrix metalloproteinase 2 binding to integrin αvβ3 by an organic molecule inhibits angiogenesis and tumor growth in vivo
Disruption of matrix metalloproteinase 2 binding to integrin αvβ3 by an organic molecule inhibits angiogenesis and tumor growth in vivo
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DOI：
10.1073/pnas.011343298
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发表时间：
2001-01-02
影响因子：
11.1
通讯作者：
Cheresh, DA
中科院分区：
文献类型：
--
作者：
Silletti, S;Kessler, T;Cheresh, DA
基质金属蛋白酶2（MMP 2）可与内皮细胞表面的整合素α（nu）β（3）结合，从而促进血管侵袭。在这里，我们描述了一种有机分子（TSRI 265），选择它的能力，结合到整合素α（nu）β（3）和阻断α（nu）β（3）与MMP 2的相互作用。虽然干扰α（nu）β（3）/MMP 2复合物的形成，但TSRI 265对α（nu）β（3）与其细胞外基质配体玻连蛋白的结合没有影响，并且不直接影响MMP 2活化或催化活性。然而，TSRI 265作为一种有效的抗血管生成剂，从而在体内阻断肿瘤生长。这些发现表明，活化的MMP 2在血管生成过程中不促进血管侵袭，除非它与内皮细胞表面的α（nu）β（3）形成复合物。通过破坏内皮细胞侵袭而不广泛抑制细胞粘附或MMP功能，化合物如TSR 1265的使用可以为与不受控制的血管生成相关的疾病提供新的治疗方法。
Matrix metalloproteinase 2 (MMP2) can associate with integrin alpha (nu)beta (3) on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin alpha (nu)beta (3) and block alpha (nu)beta (3) interaction with MMP2. Although disrupting alpha (nu)beta (3)/MMP2 complex formation, TSRI265 has no effect on alpha (nu)beta (3) binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with alpha (nu)beta (3) on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSR1265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.