Ray J M, Stetler-Stevenson W G
Extracellular Matrix Pathology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Ann N Y Acad Sci. 1994 Sep 6;732:233-47. doi: 10.1111/j.1749-6632.1994.tb24739.x.
Invasion of cells across extracellular matrix barriers requires attachment of cells to the matrix, creation of a proteolytic defect in the matrix, and migration of the cells through the defect. To date, alterations in the balance between matrix metalloproteinases (MMPs) and their inhibitors have been shown to alter cellular invasion only through effects on matrix degradation. We used a retroviral infection system to over- and underproduce tissue inhibitor of metalloproteinase-2 (TIMP-2) in human A2058 melanoma cells. Our results indicate that altering the balance of MMPs and TIMP-2 through genetic manipulation of TIMP-2 production modulates not only proteolysis of the extracellular matrix but also cell attachment to the extracellular matrix and motility of cells through matrix components. Altering the production of TIMP-2 also results in the ability of cells to form foci. These results implicate the MMPs and their inhibitors in all aspects of the cellular invasion cascade. This supports the hypothesis that highly invasive cell lines establish a balance of MMPs and inhibitors that is optimal for invasion, and alteration of this balance in either direction results in perturbation of the invasive phenotype.
细胞穿越细胞外基质屏障的侵袭过程需要细胞与基质附着、在基质中形成蛋白水解缺陷以及细胞通过该缺陷迁移。迄今为止，基质金属蛋白酶（MMPs）及其抑制剂之间平衡的改变仅通过对基质降解的影响来改变细胞侵袭。我们使用逆转录病毒感染系统在人A2058黑色素瘤细胞中过量表达和低表达金属蛋白酶组织抑制剂-2（TIMP-2）。我们的结果表明，通过对TIMP-2产生进行基因操作来改变MMPs和TIMP-2的平衡，不仅能调节细胞外基质的蛋白水解，还能调节细胞与细胞外基质的附着以及细胞通过基质成分的运动。改变TIMP-2的产生还会导致细胞形成集落的能力。这些结果表明MMPs及其抑制剂参与了细胞侵袭级联反应的各个方面。这支持了这样一种假说，即高侵袭性细胞系建立了一种对侵袭最有利的MMPs和抑制剂的平衡，而这种平衡在任何一个方向上的改变都会导致侵袭表型的紊乱。
