Hepatocyte growth factor (HGF) stimulates cell motility as well as mitotic activity of cells. High concentrations of HGF or overexpression of its cellular receptor c-Met in cancer have been reported. We analyzed the expression status of c-Met immunohistochemically in 76 cases of human esophageal cancer. Overexpression of c-Met was noted at a considerably high frequency. Intriguingly, c-Met overexpression was frequent in a specific type of cell nest formation in tumors, i.e., the small nest type, in which tumors form small, dispersed cell nests. Further immunohistochemical analyses using serial sections revealed a striking coincidence between overexpression of c-Met and its transcriptional factor, Ets-1. Overexpression of c-Met and Ets-1 was statistically more frequent in small nest type tumors. The close correlation in expression status between Ets-1 and c-Met was also confirmed using 6 established human esophageal cancer cell lines. In addition, cells that expressed high levels of Ets-1 and c-Met exhibited an extremely motile phenotype by HGF stimulation in vitro. The presence of HGF in tissue sections was confirmed using similar immunohistochemical approaches. These observations suggest that in human esophageal cancer cells the transcriptional factor Ets-1 upregulates the expression of c-Met and, consequently, confers on cells a highly motile phenotype leading to a specific form of tumor development.
Copyright 2001 Wiley-Liss, Inc.