Factor-stimulated Invasion of Carcinoma Cells Systems in Epidermal Growth Factor- and Scatter Role of the Plasminogen Activator and Matrix Metalloproteinase

Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activatoras well as that of plasminogendeficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGFor SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was trig gered atop the matrices of type I collagen or human dermal expiants in a three-dimensional culture system. During EGFor SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activatorplasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGFor SF-stimu lated cells without affecting either proteinase expression or cell molili!) across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGFor SF-stimulated tumor cells to invade interstitial matrix barriers.