INDUCTION OF HEPATOCYTE GROWTH-FACTOR IN FIBROBLASTS BY TUMOR-DERIVEDFACTORS AFFECTS INVASIVE GROWTH OF TUMOR-CELLS - IN-VITRO ANALYSIS OFTUMOR-STROMAL INTERACTIONS

Invasive and metastatic potentials of several types of carcinoma cells are regulated through interactions with host stromal cells, e.g., tum or-stromal interactions, Because hepatocyte growth factor (HGF), a lig and for the c-Met proto-oncogene product, is a mesenchymal- or stromal -derived factor that induces mitogenic, motogenic, and morphogenic res ponses, we examined the mechanisms involved in tumor-stromal interacti ons in vitro, The c-Met/HGF receptor was expressed in A431 human epide rmoid carcinoma cells, A549 human non-small cell lung cancer cells, Hu CC-T1 human cholangiocellular carcinoma cells, and SBC-3 human small c ell lung carcinoma cells. HGF stimulated cell growth, scattering, and invasion of these cells. Although these cells did not produce biologic ally significant levels of HGF, these cells did secrete soluble factor s that potently stimulated HGF production in human skin fibroblasts, T hese carcinoma cell-derived HGF inducers proved to be interleukin-1 (I L-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 fibrob lasts, HGF levels in the coculture system were much higher than the le vels in fibroblasts alone, without cocultured carcinoma cells, Togethe r with the increase in HGF levels, the number of invasive cells increa sed, 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-de rived HGF, in turn, leads to invasive growth in carcinoma cells, The m utual interactions, as mediated by HGF and HGF inducers, may play a si gnificant role in the occurrence of invasion and metastasis of carcino ma cells.