R. Swiercz et al., Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostatecancer xenografts in SCID mice, ONCOL REP, 8(3), 2001, pp. 463-470
To understand the fundamental determinants of urokinase plasminogen activat
or (uPA) driven angiogenesis in cancer we studied how inhibition of uPA act
ivity could reduce neovascularization and consequently reduce tumor size in
experimental animals. Proteolytic enzymes are required to mediate tumor ce
ll invasion to adjacent tissues and initiate the metastatic process. Many d
ifferent human cancers commonly overexpress the urokinase plasminogen activ
ator system, one of the proteolytic enzyme systems. Reduction of urokinase
activity in cancer cells is evidently associated with diminished invasion a
nd metastasis. However, it has been shown recently that inhibitors of uPA c
ould reduce tumor size also. The mechanism of action leading to decline in
tumor growth rate is not clear. Proteolysis is responsible for degradation
of proteins, for invasion or metastasis, but not for the proliferate proper
ties of the cancer cells. It is difficult to envision that diminishing the
size of tumor is due to simply blocking of uPA activity of cancer cells. In
stead, inhibitors of uPA may be interacting with the elements of the extrac
ellular matrix, such the neovascular bed surrounding tumors that has been r
eported to contain high amounts of uPA and its receptor. Overall these data
strongly suggest that inhibitors of urokinase limit cancer growth by inhib
iting angiogenesis. However, it is possible also that uPA inhibitors could
act on cancer cells directly or prevent angiogenesis by alternative mechani
sms that are not related to uPA inhibition. Therefore, we examined if plasm
inogen activator inhibitor (PAI-1) could limit angiogenesis. If it does, it
will provide definitive evidence of uPA/PAI-1 involvement in reduction of
cancer growth. Indeed, our study demonstrates that exogenously applied 14-1
b PAI-1 is a powerful inhibitor of angiogenesis in three different in vitro
models and is a powerful anti-cancer agent in a SCID mice model inoculated
with human LNCaP prostate cancer cells.