A novel host/tumor cell interaction activates matrix metalloproteinase 1 and mediates invasion through type I collagen

Along with degradation of type TV collagen in basement membrane, destructio n of the stromal collagens, types I and III, is an essential step in the in vasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)), B ecause A2058 melanoma cells produce substantial quantities of MMP-1, we use d these cells as models for studying invasion of type I collagen, With a se nsitive and quantitative in vitro invasion assay, we monitored the ability of these cells to invade a matrix of type I collagen and the ability of a s erine proteinase inhibitor and all-trans-retinoic acid to block invasion. A lthough these cells produce copious amounts of MMP-1, they do not invade co llagen unless they are cocultured with fibroblasts or with conditioned medi um derived from fibroblasts. Our studies indicate that a proteolytic cascad e that depends on stromal/tumor cell interactions facilitates the ability o f A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, parti cularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10(-6) M) suppresse s the invasion of tumor cells by several mechanisms that include suppressio n of MMP synthesis and an increase in levels of tissue inhibitor of metallo proteinases 1 and 2. We conclude that invasion of stromal collagen by A2058 melanoma cells is mediated by a novel host/tumor cell interaction in which a proteolytic cascade culminates in the activation of pro-MMP-1 and tumor cell invasion.