Tumor Development Is Retarded in Mice Lacking the Gene for Urokinase-Type Plasminogen Activator or Its Inhibitor, Plasminogen Activator Inhibitor-1
2000
In vivo tumor progression in mice with targeted
deficiencies in urokinase-type plasminogen activator
(UPA −/− ) and its inhibitor,
plasminogen activator inhibitor-1
(PAI-1 −/− ) , was studied
using a fibrosarcoma tumor model. Murine T241 fibrosarcoma cells were
s.c. implanted into three groups of mice with the following genotypes,
wild-type ( WT ),
UPA −/− , and
PAI-1 −/− . A significantly diminished
primary tumor growth in UPA −/− and
PAI-1 −/− mice occurred, relative to
WT mice. Tumors in UPA −/−
and PAI-1 −/− mice displayed lower
proliferative and higher apoptotic indices and displayed a different
neovascular morphology, as compared with WT mice. These
results are consistent with the decreased growth rates of this tumor in
these gene-deleted mice. Immunohistochemical analyses of the tumors
revealed a decrease in vascularity and vascular endothelial growth
factor expression only in tumors in
PAI-1 −/− mice. Analyses of the relative
extents of corneal angiogenesis in these same animals, induced by basic
fibroblast growth factor, corroborated the resistance of
PAI-1 −/− mice to neovascularization. The
results obtained suggest that the host fibrinolytic system plays an
important role in tumor growth in this model. Alterations in host
expression of components of this system may alter tumor growth and
dissemination by affecting the balance between tumor cell death and
proliferation, as well as extracellular matrix changes needed for
invasiveness and angiogenesis.
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