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 microg 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.
Weimar
I S
IS
Division of Immunology, Netherlands Cancer Institute, Amsterdam.
Weijer
K
K
van den Berk
P C
PC
Muller
E J
EJ
Miranda
N
N
Bakker
A Q
AQ
Heemskerk
M H
MH
Hekman
A
A
de Gast
G C
GC
Gerritsen
W R
WR
D016475:3T3 Cells; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002465:Cell Movement; D003094:Collagen; D004338:Drug Combinations; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007797:Laminin; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011509:Proteoglycans; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018411:Spodoptera / Q000378:metabolism / Q000821:virology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D017228:Hepatocyte Growth Factor; D003094:Collagen; D019859:Proto-Oncogene Proteins c-met