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Front-Cell-specific Expression of Membrane-Type 1 Matrix Metalloproteinase and Gelatinase A during Cohort Migration of Colon Carcinoma Cells Induced by Hepatocyte Growth Factor/Scatter Factor¹

Department of Pathology, Miyazaki Medical College, Miyazaki 889-1692 [K. N., T. I., Y. S., M. K.]; Department of Pathology, Keio University School of Medicine, Tokyo 160-0016 [Y. O.]; and Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108 [Y. I., M. S.], Japan

Migration of tumor cells is usually assessed as single cell locomotion in vitro using Boyden chamber type assays. In vivo, however, carcinoma cells frequently invade the surrounding tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration" and developed a two-dimensional in vitro cohort migration model, in which human rectal well-differentiated adenocarcinoma cells (L-10) migrate from piled-up cell islands as coherent sheets of cells when stimulated with hepatocyte growth factor/scatter factor. In this study, we examined whether there is a cohort migration-specific way of expression of matrix metalloproteinases (MMP) and whether degradation of extracellular matrix is necessary for this type of migration. Production of membrane-type 1-MMP (MT1-MMP) and gelatinase A (MMP-2) by L-10 cells was demonstrated by gelatin zymography, immunoblotting, and reverse transcription-PCR. When cohort migration was induced with hepatocyte growth factor/scatter factor, MT1-MMP and MMP-2 were immunolocalized predominantly in the leading edges of the front cells of migrating cell sheets, with the following cells being negative. In addition, during the cohort migration on gelatin-coated substratum, the gelatin matrix was degraded by the cells, in a very organized manner, causing radially arrayed lysis of gelatin matrix at the sites of leading edges. BB94, a synthetic inhibitor specific to MMPs, tissue inhibitor of metalloproteinases-1 and -2, and the COOH-terminal hemopexin-like domain of MMP-2 inhibited the migration on gelatin matrix. Thus, these data demonstrate that gelatin matrix is reorganized to suit cell migration via leading-edge-of-front-cell-specific localization of MT1-MMP and MMP-2 during cohort migration and suggest that the reorganization is essential for this type of migration.

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