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 receptor. The ligand for c-MET is hepatocyte growth factor (HGF), also known as scatter factor (SF), which is known to affect proliferation and motility of primarily epithelial cells. Recently, HGF/SF was also shown to affect haemopoiesis. Studies with epithelial and transfected NIH3T3 cells indicated that the HGF/SF–c-MET interaction promotes invasion in vitro and in vivo. We previously demonstrated that HGF/SF induces adhesion of c-MET-positive B-lymphoma cells to extracellular matrix molecules, and promoted migration and invasion 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 cells invaded different organs, such as liver, kidney, lymph nodes, lung, gonads 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 μg HGF/SF to mice, injected (i.v.) with c-MET-positive lymphoma cells, significantly (P = 0.018) increased the number of metastases in lung, liver and lymph nodes. In addition, HGF/SF did not significantly influence dissemination of c-MET-negative lymphoma cells (P = 0.350 with Daudi cells and 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 on endothelial cells. Finally, we investigated the effect of HGF/SF on dissemination of c-MET-transduced Ramos cells. In response to HGF/SF, c-MET-transduced Ramos cells showed an increased migration through Matrigel in Boyden chambers compared to wild-type and control-transduced Ramos cells. The dissemination pattern of c-MET-transduced cells did not differ from control cells in in vivo experiments using SCID mice. Also no effect of HGF/SF administration could be documented, in contrast to the in vitro experiments. From our experiments can be concluded that the HGF/SF–c-MET interaction only plays a minor role in the dissemination of human B-lymphoma cells. © 1999 Cancer Research Campaig

In vivo tumouricidal effects of LAD-1 monoclonal antibody on murine RL-male-1 lymphoma mediated by enhanced phagocytosis

We have reported previously that the LAD-4 monoclonal antibody (mAb) directed against a fibronectin receptor (FNR) on RL-male-1 T lymphoma cells in BALB/c mice partially inhibited their migration to the liver. In the present study, we examined the mechanism by which another anti-FNR mAb, LAD-1, exerts its antitumourigenic effects. Administration of LAD-1 significantly prolonged survival of BALB/c mice challenged previously with RL-male-1 cells. LAD-1 enhanced phagocytosis of RL-male-1 cells by hepatic macrophages and clodronate-mediated macrophage depletion abrogated the antitumour activity of LAD-1. In vitro experiments revealed that a pan-caspase inhibitor, zVAD-fmk, did not affect the ability of LAD-1 to inhibit the proliferation of RL-male-1 cells. These data suggest that the antitumour effects of LAD-1 may be dependent on stimulation of tumour cell phagocytosis and are apoptosis-independent. Thus, LAD-1-induced phagocytosis of lymphoma cells by hepatic macrophages in mice may, at least in part, be responsible for the prolonged survival of the mice