K. Matsumoto et al., HEPATOCYTE GROWTH-FACTOR IN LUNG MORPHOGENESIS AND TUMOR INVASION - ROLE AS A MEDIATOR IN EPITHELIUM-MESENCHYME AND TUMOR-STROMA INTERACTIONS, Cancer chemotherapy and pharmacology, 38, 1996, pp. 42-47
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.