MODULATION OF MOTILITY AND PROLIFERATION OF GLIOMA-CELLS BY HEPATOCYTE GROWTH-FACTOR

Invasive proliferation is a critical biological characteristic of glio mas. We evaluated the activities of hepatocyte growth factor (HGF) on proliferation and motility of glioma cells, comparing them with the ef fects of other growth factors (EGF, bFGF, PDGF-BB, TGF-beta 1). Seven primary culture lines all expressed c-met and HGF mRNA, and secreted H GF. HGF stimulated H-3-thymidine uptake of every glioma cell line (30 to 70% upregulation). Boyden chamber assay and scattering assay reveal ed that HGF promoted cell motility with chemokinetic and strong chemot actic activities. Concentric circle assay showed that HGF promoted two -dimensional expansion (proliferation and motility) mast strongly amon g the growth factors studied. Further, we analyzed 23 paraffin-embedde d sections of surgically resected gliomas (7 grade II, 8 grade III, an d 8 grade IV) by immunohistochemistry. Expression of HGF and Met incre ased with malignant progression of gliomas, suggesting that gliomas st imulated their invasive proliferation by autocrine HGF production. Neu rons and vasculature were HGF-positive, and Met-positive glioma cells gathered around them. The data indicate that neurons and vascula tore, which are the main tracks of glioma invasion, augment chemotactic inv asion and proliferation of gliomas by paracrine HFG secretion. Clearly HGF plays a critical role in invasive proliferation of glioma cells a nd it is therefore a candidate target of therapeutic intervention.