Matsumoto K, Date K, Ohmichi H, Nakamura T
Division of Biochemistry, Osaka University Medical School, Japan.
Cancer Chemother Pharmacol. 1996;38 Suppl:S42-7. doi: 10.1007/s002800051037.
Hepatocyte growth factor (HGF), a ligand for Met tyrosine kinase, is a mesenchyme- or stroma-derived multipotent factor that regulates the growth, motility, and morphogenesis of various types of cells. During lung development, Met/HGF receptor mRNA was localized in lung epithelial cells, whereas HGF mRNA was localized in lung mesenchymal cells in rat embryos. Antisense HGF oligonucleotides specifically inhibited epithelial branching morphogenesis in cultured lung rudiment isolated from day-13 rat embryos, whereas recombinant HGF stimulated branching morphogenesis. Thus, HGF seems to be at least one of the mesenchyme-derived factors that support branching morphogenesis during lung development. Together with the finding that HGF plays important roles in organogenesis and morphogenesis of organs such as the liver and kidney, HGF seems to be a mediator in epithelium-mesenchyme interactions during organogenesis. Extending the conceptual framework of epithelium-mesenchyme (or epithelium-stroma) interactions, we next examined the possible involvement of HGF in tumor-stroma interactions, because the growth and motility of carcinoma cells are regulated through their interactions with host stromal cells. HGF induced in vitro migration and invasion of GB-d1 gallbladder carcinoma cells into basement membrane components and collagen-gel matrix; however, several other growth factors did not induce marked migration and invasion of the carcinoma cells. GB-d1 cells do not produce HGF, but they produce in inducing factor for HGF production in fibroblasts; the inducing molecule was identified as interleukin 1 beta. Cocultivation of GB-d1 cells with stromal fibroblasts embedded in a collagen-gel matrix induced invasion of GB-d1 cells into the collagen gels, but invasion was inhibited by a specific antibody against HGF. This indicates that in vitro invasion of GB-d1 cells depends on stromal fibroblasts and that the fibroblast-derived invasion factor is HGF. Since HGF stimulated in vitro migration and invasion of various carcinoma cells and several carcinoma cells produced inducing factors for HGF production in stromal fibroblasts, the looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and HGF inducers may be a mechanism responsible for acquisition of the malignant phenotype through tumor-stroma interactions.
肝细胞生长因子（HGF）是一种Met酪氨酸激酶的配体，是一种间充质或基质来源的多能因子，可调节各种类型细胞的生长、运动和形态发生。在肺发育过程中，Met/HGF受体mRNA定位于肺上皮细胞，而HGF mRNA定位于大鼠胚胎的肺间充质细胞。反义HGF寡核苷酸特异性抑制从第13天大鼠胚胎分离的培养肺芽中的上皮分支形态发生，而重组HGF则刺激分支形态发生。因此，HGF似乎是肺发育过程中支持分支形态发生的至少一种间充质来源因子。连同HGF在肝脏和肾脏等器官的器官发生和形态发生中起重要作用这一发现，HGF似乎是器官发生过程中上皮-间充质相互作用的介质。扩展上皮-间充质（或上皮-基质）相互作用的概念框架，接下来我们研究了HGF在肿瘤-基质相互作用中的可能参与情况，因为癌细胞的生长和运动是通过它们与宿主基质细胞的相互作用来调节的。HGF诱导GB-d1胆囊癌细胞在体外迁移并侵入基底膜成分和胶原凝胶基质；然而，其他几种生长因子并未诱导癌细胞的明显迁移和侵袭。GB-d1细胞不产生HGF，但它们产生成纤维细胞中HGF产生的诱导因子；该诱导分子被鉴定为白细胞介素1β。将GB-d1细胞与包埋在胶原凝胶基质中的基质成纤维细胞共培养，可诱导GB-d1细胞侵入胶原凝胶，但侵袭被抗HGF特异性抗体抑制。这表明GB-d1细胞的体外侵袭依赖于基质成纤维细胞，并且成纤维细胞衍生的侵袭因子是HGF。由于HGF刺激各种癌细胞在体外迁移和侵袭，并且几种癌细胞产生基质成纤维细胞中HGF产生的诱导因子，由HGF和HGF诱导剂介导的癌细胞与基质成纤维细胞的循环相互作用可能是通过肿瘤-基质相互作用获得恶性表型的一种机制。
