The significance of urokinase-type plasminogen activator (u-PA) in tumour growth and Linomide-induced upregulation of u-PA's endogenous inhibitor PAI-2

Abstract: The progressive process of tumour invasion and generation of metastases is the primary cause of death for most patients with cancer. Some of the regulatory components of this progressive process are adhesion, migration, and proteolysis. Urokinase -type plasminogen activator (u-PA) is a serine protease associated with tissue remodelling, cellular invasiveness, matrix degradation, angiogenesis, and cell migration. It was therefore deemed important, from both a physiological and a therapeutic point of view, to investigate whether the inhibition of u-PA could suppress tumour growth. The human prostate cancer cell line DU 145 expresses high levels of u-PA in cell culture, and when the cells were inoculated subcutaneously (sc) into immunodeficient mice they grew easily as xenograft and retained their ability to produce and secrete u-PA with no detectable levels of tissue-type plasminogen activator (t-PA) or of the plasminogen activator inhibitors PAI-1 and PAI-2. It is thus a suitable in vivo model for investigating the role of u-PA in cancer. The synthetic u-PA inhibitor, p-aminobenzamidine, was found to suppress the growth of DU 145 tumours in this in vivo model as did daily sc. injections of recombinant PAI-2 (rPAI-2), the endogenous inhibitor of u-PA. Therapeutic administration of rPAI-2 over longer periods of time, however, is hardly feasible; one possible approach was therefore the upregulation of the endogenous PAI-2 production. Linomide (roquinimex), a compound previously shown to have therapeutic effects in tumour models as well as in models of autoimmunity, was found to upregulate PAI-2 in cultured human peripheral blood monocytes, both at the protein and the mRNA levels. In a study with healthy volunteers, it was shown that PAI-2 levels in monocytes were also enhanced in vivo by Linomide. Thus, in this thesis it is shown that u-PA is a significant factor for tumour growth and that the production of the u-PA’s inhibitor PAI-2 in humans can be upregulated by drugs. One strategy for anti-tumour treatment might therefore be to stimulate the endogenous production of PAI-2 in monocytes/ macrophages.