MMP-2Promotes Integrin αvβ3Mediated Adhesion And Migration Of Tumor Cells By Cleaving Fibronectin

The invasion of tumor cells in the surrounding tissue is the initial steps of tumor cell metastasis, also a complex process of highly controlled and multiple factors involved in. This process requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix, and also protease hydrolysis. Integrin family, and matrix metalloproteinases family play an important role in the process of tumor cell adhesion and migration.Matrix metalloproteinases (MMPs) can regulate the tumour microenvironment, and their expression and activation is increased in almost all human cancers compared with normal tissue. Matrix metalloproteinase-2(MMP-2) is a key regulator in the migration of tumor cells and regulates tumor cell behaviors. Integrins have been implicated in the various steps of cancer progression ranging from penetration of basement membranes, invasion of stromal tissues, entry into the circulation, to interactions with platelets and endothelial cells in the blood stream, extravasation, and outgrowth of metastatic lesions. For tumor cells to change from hyperproliferation within their normal environment towards invasive growth into the stromal compartment, they must activate proteolytic enzymes to digest basement membranes and acquire enhanced motile behavior.Integrin αvβ3has been reported to play a critical role in cell adhesion and to regulate the migration of tumor cells by promoting MMP-2activation. However, little is known about the effects of MMP-2on integrin αvβ3activity and integrin αvβ3mediated adhesion and migration of tumor cells.In this study, tumor cells were seeded using an agarose drop model and/or subjected to in vitro immunofluorescence, adhesion, migration and invasion assays to investigate the relationship between active MMP-2and integrin αvβ3in the adhesion and migration of tumor cells. We found that MMP-2was localized at the invasive front of spreading cells before integrin αvβ3. Integrin αvβ3mediated adhesion and migration of tumor cells were inhibited by a MMP-2inhibitor. MMP-2cleaved fibronectin into small fragments, which promoted the adhesion and migration of tumor cells. The results shows that MMP-2cleaved fibronectin into small fragments to enhance αvβ3mediated adhesion and migration of tumor cells. These results indicate that MMP-2may guide the direction of tumor cell migration.Based on the above conclusions, we propose the following mechanism for the initial steps of invasion based on tumor cell adhesion and migration. Active MMP-2is first recruited to the leading edge of invasive tumor cells and cleaves fibronectin into shorter fibronectin products. The fibronectin fragments promote avb3integrin recruitment to the area of cleaved fibronectin products to facilitate tumor cell adhesion and migration. Collectively, avb3integrin-mediated adhesion and migration of tumor cells is regulated, at least in part, by MMP-2via fibronectin cleavage.