Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas

Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotrophic cytokine that stimulates motility and invasion of several cancer cell types and induces angiogenesis. Its receptor MET is a transmembrane tyrosine kinase encoded by the C-MET proto-oncogene. To assess the potential relevance of SF/HGF in gliomas we performed functional studies in vivo and in vitro, expression analyses and correlative studies. We showed that both SF/HGF and MET are expressed in gliomas in vivo and are upregulated during transition from low grade to malignant glioma. When SF/HGF cDNA was transfected into glioma cells that expressed the MET receptor the cells formed considerably larger and more vascularized intracranial tumors in vivo than SF/HGF negative control clones. In other glioma cells, which constitutively expressed both SF/HGF and MET, we abolished SF/HGF expression by antisense ribozyme-targeting, which led to a significant decrease in tumorigenicity and tumor growth. In vitro SF/HGF strongly stimulated glioma cell motility and to a lesser degree proliferation. SF/HGF also strongly increased endothelial cell motility in vitro and extracts of tumors derived from SF/HGF-transfected glioma cells were more mitogenic for endothelial cells and more angiogenic in the rat cornea angiogenesis assay than extracts from control tumors. In a three-dimensional in vitro angiogenesis assay basic fibroblast growth factor (bFGF) was found to synergize with either SF/HGF or vascular endothelial growth factor (VEGF) in inducing endothelial capillary-like tubes, whereas neither SF/HGF nor VEGF alone or in combination were effective. Interestingly, while both VEGF and SF/HGF levels appeared to be increased in malignant gliomas compared with low grade ones, this was not the case for bFGF of which biologically relevant levels were already present in low grade gliomas. It thus seems that bFGF alone is insufficient to induce angiogenesis in gliomas but may act synergistically with either VEGF and/or SF/HGF when these become upregulated during malignant progression. In conclusion, we showed that SF/HGF may contribute to glioma progression by stimulating tumor invasiveness, proliferation and neovascularization.