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Effects of urokinase receptor occupancy on plasmin generation and
proteolysis of basement membrane by human tumor cells
RL Cohen, XP Xi, CW Crowley, BK Lucas, AD Levinson and MA Shuman
Cancer Research Institute, University of California-San Francisco 94143.
The goal of the present study was to assess the relative importance of
receptor-bound and secreted plasminogen activator urokinase (u-PA) in
generating cell-surface plasmin and fostering destruction of normal tissue
by tumor cells. We first showed that active site-inhibited u-PA could
displace endogenous u-PA from the surface of the human colon adenocarcinoma
cell line HCT 116. We then prepared expression vectors for u-PA and for a
mutant molecule in which the codon for the active site serine residue was
changed to encode alanine. Expression of non- functional mutant u-PA
decreased the level of cell-bound active u-PA by more than 95% via a
mechanism that involved competition for receptor sites. Decreased
cell-surface u-PA activity was associated with a decrease in cell-bound
plasmin activity to undetectable levels, suggesting that receptor-bound
u-PA plays an important role in the generation of plasmin on the cell
surface. Transfectants that secreted eightfold to 20-fold elevated levels
of active wild-type u-PA showed approximately 50% increases in
cell-associated u-PA and only twofold to fourfold increases in
cell-associated plasmin, suggesting that the role of secreted u-PA in
generating cell-surface plasmin activity was relatively minor. In parent
cells and both types of transfectants there was a good correlation between
the amount of plasmin bound to the tumor cell surface and the extent to
which a basement membrane substrate was degraded. These studies show that
receptor-bound u-PA provides an efficient mechanism for plasmin generation
on the surface of tumor cells, which, in turn, contributes significantly to
their degradative potential.
Volume 78,
Issue 2,
pp. 479-487,
07/15/1991
Copyright © 1991 by The American Society of Hematology
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