HEPATOCYTE GROWTH-FACTOR IN LUNG MORPHOGENESIS AND TUMOR INVASION - ROLE AS A MEDIATOR IN EPITHELIUM-MESENCHYME AND TUMOR-STROMA INTERACTIONS

Hepatocyte growth factor (HGF), a ligand for Met tyrosine kinase, is a mesenchyme- or stroma-derived multipotent factor that regulates the g rowth, motility, and morphogenesis of various types of cells. During l ung development, Met/HGF receptor mRNA was localized in lung epithelia l cells, whereas HGF mRNA was localized in lung mesenchymal cells in r at embryos. Antisense HGF oligonucleotides specifically inhibited epit helial branching morphogenesis in cultured lung rudiment isolated from day-13 rat embryos, whereas recombinant HGF stimulated branching morp hogenesis. Thus, HGF seems to be at least one of the mesenchyme-derive d factors that support branching morphogenesis during lung development . Together with the finding that HGF plays important roles in organoge nesis and morphogenesis of organs such as the liver and kidney, HGF se ems to be a mediator in epithelium-mesenchyme interactions during orga nogenesis. Extending the conceptual framework of epithelium-mesenchyme (or epithelium-stroma) interactions, we next examined the possible in volvement of HGF in tumor-stroma interactions, because the growth and motility of carcinoma cells are regulated through their interactions w ith host stromal cells. HGF induced in vitro migration and invasion of GB-dl gallbladder carcinoma cells into basement membrane components a nd collagen-gel matrix; however, several other growth factors did not induce marked migration and invasion of the carcinoma cells. GB-dl cel ls do not produce HGF, but they produce an inducing factor for HGF pro duction in fibroblasts; the inducing molecule was identified as interl eukin 1 beta. Cocultivation of GB-dl cells with stromal fibroblasts em bedded in a collagen-gel matrix induced invasion of GB-dl cells into t he collagen gels, but invasion was inhibited by a specific antibody ag ainst HGF. This indicates that in vitro invasion of GB-dl cells depend s on stromal fibroblasts and that the fibroblast-derived invasion fact or is HGF. Since HGF stimulated in vitro migration and invasion of var ious carcinoma cells and several carcinoma cells produced inducing fac tors for HGF production in stromal fibroblasts, the looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and HGF in ducers may be a mechanism responsible for acquisition of the malignant phenotype through tumor-stroma interactions.