Matrix metalloproteinase-2 contributes to cancer cell migration on collagen.
Matrix metalloproteinase-2 contributes to cancer cell migration on collagen.
复制标题
DOI：
10.1158/0008-5472.130.65.1
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Xiaoping Xu;Yao Wang;Zhihua Chen;M. Sternlicht;M. Hidalgo;B. Steffensen
中科院分区：
文献类型：
--
作者：
Xiaoping Xu;Yao Wang;Zhihua Chen;M. Sternlicht;M. Hidalgo;B. Steffensen
随着肿瘤的扩大和转移，基质金属蛋白酶(MMPs)是癌细胞穿透组织的中心，但MMP2促进癌细胞迁移的机制尚不清楚。在目前的实验中，一种广谱的基质金属蛋白酶抑制剂和从基质金属蛋白酶-2中分离的胶原结合域(CBD)都能抑制细胞在天然I型胶原上的迁移。这些结果从总体上证实了MMPs的参与，并表明MMP2通过参与MMP2与胶原蛋白的相互作用促进细胞迁移。为了排除基质金属蛋白酶-9的潜在重叠效应，额外的实验表明，基质金属蛋白酶-2也促进了基质金属蛋白酶-9-/-细胞的迁移。为了研究来自人纤维连接蛋白的同源CBD是否也抑制细胞迁移，我们首先证明了纤维连接蛋白的断裂是乳腺癌肿瘤的一个特征，并且有几个片段包含CBD。然而，重组纤维连接蛋白结构域不改变细胞在胶原上的迁移。这种对细胞迁移的影响在竞争性蛋白-蛋白结合分析中得到了探索，这表明基质金属蛋白酶-2对胶原的亲和力超过纤维连接蛋白。此外，虽然分离的基质金属蛋白酶-2 CBD抑制明胶溶解活性的基质金属蛋白酶-2和肿瘤提取物，这种抑制不是相应的纤维连接蛋白结构域的特征。综上所述，我们的结果提供了证据，证明基质金属蛋白酶-2是癌细胞行为的重要决定因素，但不受纤维连接蛋白的胶原结合片段的抑制。
Matrix metalloproteinases (MMP) are central to tissue penetration by cancer cells, as tumors expand and form metastases, but the mechanism by which MMP-2 contributes to cancer cell migration is not well understood. In the present experiments, both a broad-spectrum MMP inhibitor and the isolated collagen binding domain (CBD) from MMP-2 inhibited cell migration on native type I collagen. These results verified the involvement of MMPs in general and showed that MMP-2, specifically, contributes to cell migration by a mechanism involving MMP-2 interaction with collagen. To exclude potential overlapping effects of MMP-9, additional experiments showed that MMP-2 also contributed to migration of MMP-9-/- cells. To investigate whether the homologous CBD from human fibronectin also inhibited cell migration, we first showed that fragmentation of fibronectin is a feature of breast cancer tumors and that several fragments contained the CBD. However, the recombinant fibronectin domain did not alter cell migration on collagen. This lack of effect on cell migration was explored in competitive protein-protein binding assays, which showed that the affinity of MMP-2 for collagen exceeds that of fibronectin. Furthermore, whereas the isolated MMP-2 CBD inhibited the gelatinolytic activities of MMP-2 and tumor extracts, such an inhibition was not characteristic of the corresponding fibronectin domain. Together, our results provide evidence that MMP-2 is an important determinant of cancer cell behavior but is not inhibited by the collagen binding segment of fibronectin.