Analysis of mechanisms involved in cohort migration of human colon carcinoma cells

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(I) Mechanisms of localized release from cell-cell adhesion during cohort migrationDuring cohort migration (CM) induced by hepatocyte growth factor/scatter factor (HGF/SF), migrating cells show localized release from cell-cell adhesion in the lower portion of the cells. This enables cells to extend leading edges and hence move. This localized release was associated with binding of IQGAP-1 to the E-cadherin/catenin complex. This caused release of α-catenin, which connects E-cadherin to actin filament cell skeleton, from the complex. This mechanism is now under investigation more in detail using dominant active/negative Rac 1 or cdc42-transfected cells.(ii) Enhanced induction of cohort migration of carcinoma cells in the co-presence of fibroblastsWe made in vitro CM assays which are more similar to the in vivo situation by coculturing carcinoma cells with fibroblasts. Coexistence of fibroblasts enhanced HGF/SF-induced CM of carcinoma cells. In the coculture, carcinoma cells stimulated secretion of TGF-β1 by fibroblasts, and the increased TGF-β1 induced more production of motility-stimulating EDA-containing fibronectin by cells. Thus, cell-cell interaction is shown to play an important role in CM..(iii) Front-cell-specific expression of matrix metalloproteinases (MMP) during cohort migrationDuring HGF/SF-induced CM, gelatinase A (GelA) and membrane type-1 matrix metalloproteinase (MT1-MMP) were positively demonstrated predominantly in front cells of the migrating sheets, with the following cells being negative. These MMPs caused rearrangement of gelatin matrix, which was essential for CM. Since the above front-cell-specific expression pattern of MMPs was effaced when scattering (single cell locomotion) of cells was induced instead of CM, cell-cell contact in migrating cell sheets appeared responsive for the pattern.