Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.
Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.
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基质金属蛋白酶-1（MMP-1）是肿瘤发生、炎症和组织重塑的重要介质，其降解关键基质成分的能力。最近的研究表明，基质来源的MMP 1可能发挥直接的致癌活性，通过蛋白酶激活受体1（PAR 1）在癌细胞中的信号转导，然而，这还没有在体内建立。我们产生了一个Mmp 1a基因敲除小鼠，以确定是否基质衍生的Mmp 1a影响肿瘤生长。Mmp 1a缺陷小鼠大体正常，出生时为孟德尔比率，然而，Mmp 1a缺陷导致肺肿瘤的生长和血管生成显著降低。肺癌细胞与野生型Mmp 1a +/+成纤维细胞的共植入完全恢复了Mmp 1a缺陷动物的肿瘤生长，突出了基质来源的Mmp 1a的关键作用。肺癌细胞中PAR 1表达的沉默表型模仿基质Mmp 1a缺陷，从而验证肿瘤来源的PAR 1作为Mmp 1a靶点。Mmp 1a的分泌受其前结构域抑制自切割的能力控制，而人MMP 1由于稳定的前结构域和催化结构域相互作用而有效分泌。总之，这些数据表明基质Mmp 1a驱动体内肿瘤发生，并提供了靶向MMP 1-PAR 1轴可以提供有效治疗肺癌的概念验证。
Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells, however, this has not been established in vivo. We generated a Mmp1a knock-out mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios, however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Co-implantation of lung cancer cells with wild-type Mmp1a+/+ fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as a Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to suppress auto-cleavage, whereas human MMP1 is efficiently secreted due to stable pro- and catalytic domain interactions. Together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof-of-concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer.
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