A Novel Host/Tumor Cell Interaction Activates Matrix Metalloproteinase 1 and Mediates Invasion through Type I Collagen

Abstract

Along with degradation of type IV collagen in basement membrane, destruction of the stromal collagens, types I and III, is an essential step in the invasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)). Because A2058 melanoma cells produce substantial quantities of MMP-1, we used these cells as models for studying invasion of type I collagen. With a sensitive 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 serine proteinase inhibitor and all-trans-retinoic acid to block invasion. Although these cells produce copious amounts of MMP-1, they do not invade collagen unless they are cocultured with fibroblasts or with conditioned medium derived from fibroblasts. Our studies indicate that a proteolytic cascade that depends on stromal/tumor cell interactions facilitates the ability of A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, particularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10 ؊6 M) suppresses the invasion of tumor cells by several mechanisms that include suppression of MMP synthesis and an increase in levels of tissue inhibitor of metalloproteinases 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.

MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices

“…In further support of such findings, a recent study showed that increased MMP-1 expression in human melanoma tumors correlated with tumor regression and a better clinical outcome (Nikkola et al, 2001). MMP-1 has also been reported to be a positive regulator of tumor invasion and keratinocyte migration (Benbow et al, 1999;Brinckerhoff et al, 2000;Dumin et al, 2001;Pilcher et al, 1997;Pilcher et al, 1998). Thus, MMP-1 and other MMPs appear to stimulate cell behaviors that are associated with tumor invasion and progression (Egeblad and Werb, 2002).…”

RNA Interference Inhibition of Matrix Metalloproteinase-1 Prevents Melanoma Metastasis by Reducing Tumor Collagenase Activity and Angiogenesis

“…MMP-1 mediates the invasion of melanoma cells through type I collagen in vitro (21,22), and this is largely attributed to the ability of MMP-1 to degrade the collagen surrounding the cells (27). To test the ability of each shRNA cell line to degrade type I collagen, cells were plated into an in vitro collagen destruction assay (24).…”

“…Melanoma expresses several different MMPs, and their expression pattern changes throughout the different stages of melanoma progression (17,18), with MMP-2, which degrades the type IV collagen of basement membrane, being frequently linked to an invasive phenotype (19,20). MMP-1 has not been well studied in melanoma progression, although its primary substrate, type I collagen, is a major component of the dermal layer of skin, and MMP-1 expression is necessary for melanoma cell invasion through synthetic ECMs in vitro (21)(22)(23).…”

Short Hairpin RNA–Mediated Inhibition of Matrix Metalloproteinase-1 in MDA-231 Cells: Effects on Matrix Destruction and Tumor Growth

“…In a differentiated epithelial cell line (MadinDarby canine kidney cells), overexpressing proMMP-1 did not confer an invasive phenotype in an in vitro peritoneal invasion model or in a three-dimensional collagen matrix, perhaps because these cells did not express the proteinases needed to fully activate the latent enzyme (3,(12)(13)(14). However, when MMP-1 was overexpressed in the skin of transgenic mice, it increased their susceptibility to skin carcinogenesis (15).…”