The c-Met receptor and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly overexpressed in malignant gliomas. Signaling through c-Met as well as exposure to hypoxia can stimulate glioma cell migration and invasion. In several cancer cell types, hypoxia was shown to activate the c-met promoter, which contains hypoxia inducible factor-1 (HIF-1) binding sites. We hypothesized that hypoxia might upregulate c-Met also in glioma cells. Analyzing 18 different glioblastoma cell lines and 10 glioblastoma primary cultures, we found that in 50% of both the cell lines and the primary cultures c-Met protein levels were increased following exposure to hypoxia. Upregulation of c-met in response to hypoxia was also detected at the transcriptional level. In all primary cultures and in 16 of the 18 cell lines (89%), HIF-1 alpha levels were increased by hypoxia. Transfection of siRNA against HIF-1 alpha abgrogated the hypoxic induction of c-Met, suggesting that c-Met expression is upregulated by a HIF-1 alpha-dependent mechanism. Hypoxia sensitized glioblastoma cell lines which showed hypoxic induction of c-Met to the motogenic effects of SF/HGF. These findings suggest that approximately half of all human glioblastomas respond to hypoxia with an induction of c-Met, which can enhance the stimulating effect of SF/HGF on tumor cell migration.
