HGF/SF and its receptor c-MET play a minor role in the dissemination of human B-lymphoma cells in SCID mice

The MET protooncogene, c-MET, encodes a cell surface tyrosine kinase recept or. The ligand for c-MET is hepatocyte growth factor (HGF), also known as s catter factor (SF), which is known to affect proliferation and motility of primarily epithelial cells. Recently, HGF/SF was also shown to affect haemo poiesis. Studies with epithelial and transfected NIH3T3 cells indicated tha t the HGF/SF-c-MET interaction promotes invasion in vitro and in vivo. We p reviously demonstrated that HGF/SF induces adhesion of c-MET-positive B-lym phoma cells to extracellular matrix molecules, and promoted migration and i nvasion in in vitro assays. Here, the effect of HGF/SF on tumorigenicity of c-MET-positive and c-MET-negative human B-lymphoma cell lines was studied in C.B-17 scid/scid (severe combined immune deficient) mice. Intravenously (i.v.) injected c-MET-positive (BJAB) as well as c-MET-negative (Daudi and Ramos cells) B-lymphoma cells formed tumours in SCID mice. The B-lymphoma c ells invaded different organs, such as liver, kidney, lymph nodes, lung, go nads and the central nervous system. We assessed the effect of human HGF/SF on the dissemination of the B-lymphoma cells and found that administration of 5 mu g HGF/SF to mice, injected (i.v.) with c-MET-positive lymphoma cel ls, significantly (P = 0.018) increased the number of metastases in lung, l iver and lymph nodes. In addition, HGF/SF did not significantly influence d issemination of c-MET-negative lymphoma cells (P = 0.350 with Daudi cells a nd P = 0.353 with Ramos cells). Thus the effect of administration of HGF/SF on invasion of lymphoma cells is not an indirect one, e.g. via an effect o n endothelial cells. Finally, we investigated the effect of HGF/SF on disse mination of c-MET-transduced Ramos cells. In response to HGF/SF, c-MET-tran sduced Ramos cells showed an increased migration through Matrigel in Boyden chambers compared to wild-type and control-transduced Ramos cells. The dis semination pattern of c-MET-transduced cells did not differ from control ce lls in in vivo experiments using SCID mice. Also no effect of HGF/SF admini stration could be documented, in contrast to the in vitro experiments. From our experiments can be concluded that the HGF/SF-c-MET interaction only pl ays a minor role in the dissemination of human B-lymphoma cells.