Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice

Abstract

To understand the fundamental determinants of urokinase plasminogen activator (uPA) driven angiogenesis in cancer we studied how inhibition of uPA activity could reduce neovascularization and consequently reduce tumor size in experimental animals. Proteolytic enzymes are required to mediate tumor cell invasion to adjacent tissues and initiate the metastatic process. Many different human cancers commonly overexpress the urokinase plasminogen activator system, one of the proteolytic enzyme systems. Reduction of urokinase activity in cancer cells is evidently associated with diminished invasion and metastasis. However, it has been shown recently that inhibitors of uPA could 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 properties 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. Instead, inhibitors of uPA may be interacting with the elements of the extracellular matrix, such the neovascular bed surrounding tumors that has been reported to contain high amounts of uPA and its receptor. Overall these data strongly suggest that inhibitors of urokinase limit cancer growth by inhibiting angiogenesis. However, it is possible also that uPA inhibitors could act on cancer cells directly or prevent angiogenesis by alternative mechanisms that are not related to uPA inhibition. Therefore, we examined if plasminogen 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 14-1b 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.