Role of fibroblasts in HGF/SF-induced cohort migration of human colorectalcarcinoma cells: Fibroblasts stimulate migration associated with increasedfibronectin production via upregulated TGF-beta 1

Carcinoma cells frequently invade the surrounding tissue as coherent cluste rs or nests of cells. We have called this type of movement "cohort migratio n." We have previously presented an in vitro two-dimensional cohort migrati on model, in which highly metastatic variant L-10 cells of human rectal ade nocarcinoma cell line RCM-1 moved as coherent cell sheets when stimulated w ith 12-O-tetradecanoylphorbol-13-acetate (TPA) or hepatocyte growth factor/ scatter factor (HGF/SF). Pericellular deposition of EDA-containing fibronec tin (EDA+FN) was essential for TPA-induced cohort migration. In this study, we investigated how colon-derived fibroblasts could affect the induction o f cohort migration of colorectal carcinoma cells by HGF/SF, since carcinoma cell-fibroblast interactions frequently regulate biological events during cancer cell invasion. Fibroblasts co cultured with L-10 carcinoma cells sti mulated HGF/SF-induced cohort migration of L-10 cells up to 2 to 3-fold. Co nditioned medium (CM) from fibroblasts that were cultured alone was not eff ective but CM from fibroblasts cocultured with carcinoma cells enhanced HGF /SF-induced cohort migration, and this effect in CM was found to be mediate d by TGF-beta 1 upregulated in co-cultured conditions. Among the motogenic growth factors examined, only TGF-beta 1 synergistically stimulated HGF/SF- induced L-10 cell cohort migration, although TGF-beta 1 alone did not induc e cohort migration. TGF-beta 1 also exhibited synergistic effect in several other human colorectal carcinoma cell lines. The synergistic stimulation o f L-10 cell cohort migration by HGF/SF and TGF-PI was associated with incre ased production of motility-enhancing EDA+FN by L-10 cells, and blocking FN with a specific antibody effectively inhibited the synergistic effect. Int . J. Cancer 82:449-458, 1999. (C) 1999 Wiley-Liss, Inc.