Cohort migration of carcinoma cells: Differentiated colorectal carcinoma cells move as coherent cell clusters or sheets

Active migration of tumor cells is usually assessed as single cell locomoti on in vitro using Boyden chamber-type assays. In vivo, however, carcinoma c ells, malignant cells of epithelial origin, frequently invade the surroundi ng tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration". In our work, the invasion front of colon ca rcinomas consisted of compact tumor glands, partially resolved glands or ma rkedly resolved glands with scattered tumor cell clusters or single cells l ying ahead. In the former two types, which constituted about a half of all cases, cohort migration seems to be the predominant mechanism, whereas both cohort migration and single cell locomotion may be involved in the last on e. In this light, it is very advantageous to investigate the mechanisms inv olved in the cohort migration. In this review, we present a two-dimensional motility assay as a cohort mig ration model, in which human colorectal carcinoma cells move outwards from the cell islands mainly as localized coherent sheets of cells when stimulat ed with 12-O-tetradecanoylphorbol-13-acetate (TPA) or hepatocyte growth fac tor/scatter factor (HGF/SF). Within the migrating cell sheets, wide interce llular gaps occur at the lower portion of the cells to allow the cells to e xtend leading lamellae forward while close cell-cell contacts remain at the upper portion of the cells. This localized modulation of cell-cell adhesio n at the lower portion of the cells is associated with increased tyrosine p hosphorylation of the E-cadherin-catenin complex in TPA-induced cohort migr ation and with reduced alpha-catenin complexed with E-cadherin in HGF/SF-in duced cohort migration. Furthermore, fibronectin deposited by migrating cel ls is essential for their movement, and on the gelatin-coated substrate eve n degradation and remodeling of the substrate by matrix metalloproteinases are also needed. Thus, in cohort migration it is likely that cells are rele ased from cell-cell adhesion only at the lower portion of the cells via mod ulation of E-cadherin-catenin-based mechanism, and this change allows the c ells to extend leading lamellae onto the extracellular matrix substrate rem odeled by deposition of fibronectin and organized digestion.