In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor scatter factor

OBJECTIVE: Considered as immune effector cells of the central nervous syste m, microglia represent a major component of the inflammatory cells found in malignant gliomas. Although their role in brain tumor biology is unclear, accumulation of microglia in malignant brain tumors may be mediated through active secretion of cytokines by glioma cells. Because hepatocyte growth f actor/scatter factor (HCF/SF) has been shown to modulate glioma motility th rough an autocrine mechanism, and because microglia have been reported to e xpress the HGF/SF receptor Met, we hypothesized that microglia recruitment by gliomas may also occur through the secretion of HGF/SF. METHODS: The effect of glioma cells in augmenting BV-2 murine microglia mot ility was studied by using an in vitro Boyden chamber migration assay. To d etermine the chemokines involved in microglia migration, neutralizing monoc lonal antibodies against monocyte chemotactic protein-1 and HGF/SF were tes ted. Immunoblotting was used to check for the expression of HCF/SF by gliom a cells, and the expression of Met by BV-2 cells was examined by flow cytom etry. RESULTS: BV-2 migration was noted within 7 hours of incubation with both hu man (U251 MG and U373 MG) and murine (GL261) glioma cell lines. This migrat ion corresponded to HGF/SF secretion by glioma cells and was completely inh ibited by neutralizing monoclonal antibody against HGF/SF, but not monocyte chemotactic protein-1. Exposure of BV-2 cells to recombinant HCF/SF, but n ot monocyte chemotactic protein-1, resulted in their migration and down-reg ulation of Met in a dose-dependent fashion. CONCLUSION: HGF/SF, which plays a role in glioma motility and mitogenesis, may also act as a chemokine for microglia and may be responsible for the mi croglia infiltration in malignant gliomas. This active recruitment of micro glia may play an important role in glioma biology.