ENHANCED TUMORIGENICITY AND INVASION-METASTASIS BY HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR-MET SIGNALING IN HUMAN-CELLS CONCOMITANT WITH INDUCTION OF THE UROKINASE PROTEOLYSIS NETWORK
M. Jeffers et al., ENHANCED TUMORIGENICITY AND INVASION-METASTASIS BY HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR-MET SIGNALING IN HUMAN-CELLS CONCOMITANT WITH INDUCTION OF THE UROKINASE PROTEOLYSIS NETWORK, Molecular and cellular biology, 16(3), 1996, pp. 1115-1125
Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effe
ctor of cells expressing the Met tyrosine kinase receptor. Although HG
F/SF is synthesized by mesenchymal cells and acts predominantly on epi
thelial cells, we have recently demonstrated that human sarcoma cell l
ines often inappropriately express high levels of Met and respond mito
genically to HGF/SF. In the present report we show that HGF/SF-Met sig
nalling in the human leiomyosarcoma cell line SK-LMS-1 enhances its in
vivo tumorigenicity, an effect for which the mitogenicity of this sig
nalling pathway is likely to play a role. In addition, we found that H
GF/SF-Met signalling dramatically induces the in vitro invasiveness an
d in vivo metastatic potential of these cells. We have studied the mol
ecular basis by which HGF/SF-Met signalling mediates the invasive phen
otype. A strong correlation has previously been demonstrated between t
he activation of the urokinase plasminogen activator (uPA) proteolysis
network and the acquisition of the invasive-metastatic phenotype, and
we show here that HGF/SF-Met signalling significantly increases the p
rotein levels of both uPA and its cellular receptor in SK-LMS-1 cells.
This results in elevated levels of cell-associated uPA and enhanced p
lasmin generating ability by these cells. These studies couple HGF/SF-
Met signalling to the activation of proteases that mediate dissolution
of the extracellular matrix basement membrane, an important property
for cellular invasion-metastasis.