Is. Weimar et al., HGF/SF and its receptor c-MET play a minor role in the dissemination of human B-lymphoma cells in SCID mice, BR J CANC, 81(1), 1999, pp. 43-53
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.