Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αVβ3 integrin
Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αVβ3 integrin
复制标题
DOI：
10.1016/s1535-6108(03)00133-8
复制
发表时间：
2003-06-01
期刊：
影响因子：
50.3
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Hamano, Y;Zeisberg, M;Kalluri, R
我们证明了肿瘤抑制素的生理作用，IV型胶原蛋白（Col IValpha 3）的α 3链的裂解片段，这是存在于循环中。具有Col IVa 3基因缺失的小鼠显示与增强的病理性血管生成相关的加速的肿瘤生长，而与发育和组织修复相关的血管生成不受影响。用重组tumstatin补充科尔IVal α 3缺陷小鼠至正常生理浓度消除了肿瘤生长速率的增加。肿瘤抑制素的抑制作用需要在病理性而非生理性血管生成血管上表达的α V β 3整联蛋白。基质金属蛋白酶-9（其有效地从Col IVal α 3切割tumstatin）缺陷的小鼠具有减少的循环tumstatin和加速的肿瘤生长。这些结果表明MMP产生的基底膜胶原片段可以作为整合素介导的病理性血管生成和肿瘤生长的抑制因子具有内源性功能。
We demonstrate a physiological role for tumstatin, a cleavage fragment of the alpha3 chain of type IV collagen (Col IValpha3), which is present in the circulation. Mice with a genetic deletion of Col IVa3 show accelerated tumor growth associated with enhanced pathological angiogenesis, while angiogenesis associated with development and tissue repair are unaffected. Supplementing Coll IValpha3-deficient mice with recombinant tumstatin to a normal physiological concentration abolishes the increased rate of tumor growth. The suppressive effects of tumstatin require alphaVbeta3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels. Mice deficient in matrix metalloproteinase-9, which cleaves tumstatin efficiently from Col IValpha3, have decreased circulating tumstatin and accelerated growth of tumor. These results indicate that MMP-generated fragments of basement membrane collagen can have endogenous function as integrin-mediated suppressors of pathologic angiogenesis and tumor growth.