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 ind uces angiogenesis. Its receptor MET is a transmembrane tyrosine kinase enco ded by the C-MET proto-oncogene. To assess the potential relevance of SF/HG F in gliomas we performed functional studies in vivo and in vitro, expressi on analyses and correlative studies. We showed that both SF/HGF and MET are expressed in gliomas in vivo and are upregulated during transition from lo w grade to malignant glioma. When SF/HGF cDNA was transfected into glioma c ells that expressed the MET receptor the cells formed considerably larger a nd more vascularized intracranial tumors in vivo than SF/HGF negative contr ol clones. In other glioma cells, which constitutively expressed both SF/HG F 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 degre e proliferation. SF/HGF also strongly increased endothelial cell motility i n vitro and extracts of tumors derived from SF/HGF-transfected glioma cells were more mitogenic for endothelial cells and more angiogenic in the rat c ornea angiogenesis assay than extracts from control tumors. In a three-dime nsional in vitro angiogenesis assay basic fibroblast growth factor (bFGF) w as found to synergize with either SF/HGF or Vascular endothelial growth fac tor (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 c ompared with low grade ones, this was not the case for bFGF of which biolog ically relevant levels were already present in low grade gliomas. It thus s eems that bFGF alone is insufficient to induce angiogenesis in gliomas but may act synergistically with either VEGF and/or SF/HGF when these become up regulated during malignant progression. In conclusion, we showed that SF/HG F may contribute to glioma progression by stimulating tumor invasiveness; p roliferation and neovascularization. (C) 1999 ISDN. Published by Elsevier S cience Ltd. All rights reserved.