SCATTER FACTOR EXPRESSION AND REGULATION IN HUMAN GLIAL TUMORS

Scatter factor (SF) (also known as hepatocyte growth factor [HGF]) is a cytokine that induces cell motility in vitro and angiogenesis in viv o. SF appears to be a determinant of the malignant phenotype in certai n systemic cancers. We detected SF in extracts prepared from human gli omas, with the highest levels found in malignant tumors. Human gliobla stoma cells expressed both SF and its receptor (c-met protein) in vivo , as demonstrated by immunohistochemistry. Consistent with these obser vations, we found moderate to high levels of production of immunoreact ive and biologically active SF by cultured human glioblastoma cells (3 of 8 lines) and by neural microvascular endothelial cells (NMVEC) (3 of 3 lines). Sf stimulated the proliferation of glioblastoma and NMVEC cell lines by paracrine or autocrine mechanisms, Conditioned medium ( CM) from both glioblastoma and NMVEC cells contained Sf-inducing facto r (SF-IF) activity, defined by its ability to stimulate SF production in an indicator cell line (MRCS human fibroblasts). This activity cons isted of a high-molecular-weight (> 30 kDa), heat-sensitive component and a low-molecular weight (< 30 kDa), heat-stable component. Furtherm ore, glioblastoma CM stimulated NMVEC SF production, and NMVEC CM stim ulated glioblastoma cell SF production, by 3- to 6-fold in each case. Our findings demonstrate that SF-dependent interactions between glioma cells, and between glioma cells and endothelium, can contribute to th e heterogeneous proliferative and angiogenic phenotypes of malignant g liomas in vivo. (C) 1996 Wiley-Liss, Inc.