Until recently, tumor progression has been considered a multistep process defined by tumor cell mutations and the importance of the surrounding stroma poorly understood. It is now recognized that matrix-degrading enzymes that promote tumor cell invasion are elaborated by both tumor cells and fibroblasts in vivo. To determine the relative role of tumor cell-derived proteases compared with fibroblast-derived proteases, coculture experiments were done with each cell type using an in vitro model of type 1 collagen degradation. Head and neck squamous cell carcinoma cells in coculture with normal dermal fibroblasts showed matrix degradation, but neither cell type alone produced this effect. Manipulating the in vitro coculture environment showed that collagenolysis in this model was a result of fibroblast-derived matrix metalloproteases (MMP). To explore the possible role of extracellular matrix metalloprotease inducer (EMMPRIN) in this interaction, transfection of EMMPRIN into a cell line with low endogenous EMMPRIN expression was done and showed a significant increase in collagenolysis. Inhibition of collagenolysis with a tissue inhibitor of metalloprotease-2 (TIMP-2) and a synthetic furin inhibitor was observed but not with TIMP-1, which suggested a possible role for membrane type-1 MMP. These results suggest that fibroblast-derived MMPs but not those from tumor cells are important for in vitro collagenolysis and that this process is promoted by tumor cell-expressed EMMPRIN. Copyright © 2005 American Association for Cancer Research.