ROLE OF THE PLASMINOGEN-ACTIVATOR AND MATRIX METALLOPROTEINASE SYSTEMS IN EPIDERMAL-GROWTH-FACTOR-STIMULATED AND SCATTER-FACTOR-STIMULATED INVASION OF CARCINOMA-CELLS

Normal as well as neoplastic cells traverse extracellular matrix barri ers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter f actor (SF)-c-Met interactions, The plasminogen activator-plasminogen a xis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasm inogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. T o characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-S CC-1) was triggered atop the matrices of type I collagen or human derm al explants in a three-dimensional culture system. During EGF- or SF-i nduced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen a ctivator (uPA) and uPA receptor as well as the matrix metalloproteinas es (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gela tinase B. Despite the presence of a positive correlation between uPA r eceptor-uPh expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasmino gen activator-plasminogen axis. In contrast, both recombinant and synt hetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can direc tly regulate the ability of either EGF- or SF-stimulated tumor cells t o invade interstitial matrix barriers.