Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions.

Invasive and metastatic potentials of several types of carcinoma cells are regulated through interactions with host stromal cells, e.g., tumor-stromal interactions. Because hepatocyte growth factor (HGF), a ligand for the c-Met proto-oncogene product, is a mesenchymal- or stromal-derived factor that induces mitogenic, motogenic, and morphogenic responses, we examined the mechanisms involved in tumor-stromal interactions in vitro. The c-Met/HGF receptor was expressed in A431 human epidermoid carcinoma cells, A549 human non-small cell lung cancer cells, HuCC-T1 human cholangiocellular carcinoma cells, and SBC-3 human small cell lung carcinoma cells. HGF stimulated cell growth, scattering, and invasion of these cells. Although these cells did not produce biologically significant levels of HGF, these cells did secrete soluble factors that potently stimulated HGF production in human skin fibroblasts. These carcinoma cell-derived HGF inducers proved to be interleukin-1 (IL-1) in A431 cells, IL-1 plus basic fibroblast growth factor (bFGF) in A549 and HuCC-T1 cells, and bFGF plus platelet-derived growth factor in SBC-3 cells. When these carcinoma cells were cocultured with fibroblasts, HGF levels in the coculture system were much higher than the levels in fibroblasts alone, without cocultured carcinoma cells. Together with the increase in HGF levels, the number of invasive cells increased, but in vitro invasion of carcinoma cells in the coculture system was strongly inhibited by anti-HGF antibodies. Thus, there are mutual interactions between carcinoma cells and fibroblasts: IL-1, bFGF, and platelet-derived growth factor derived from tumor cells play a role in inducing HGF expression in stromal fibroblasts, whereas fibroblast-derived HGF, in turn, leads to invasive growth in carcinoma cells. The mutual interactions, as mediated by HGF and HGF inducers, may play a significant role in the occurrence of invasion and metastasis of carcinoma cells.