Plasminogen activator system modulates invasive capacity and proliferationin prostatic tumor cells

The malignant phenotype of prostatic tumor cells correlates with the expres sion of both uPA and its cell-membrane receptor (uPAR); however, there is l ittle information concerning the role of cell-bound uPA in matrix degradati on and invasion. Our results suggest that ceh-associated uPA plays a key ro le in regulating the amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differential production of uPA corresp onds with the capacity to bind and activate plasminogen, In addition, we pr ovide direct evidence that both uPA secretion and the presence of uPA-uPAR complexes characterize the invasive phenotype of PRCA cells and suggest the existence of several pathways by which tumor cells acquire plasmin activit y, LNCaP cells (which do not produce uPA but express uPAR) may activate pla smin through exogenous uPA, In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observed in several other systems. PAI-I accumulation in the conditioned medium (CM) limits plasmin action to the pe ricellular microenviromnent, Our results indicate that MMP-9 and MMP-2 are also activated by plasmin generated by cell-bound but not by soluble, extra cellular uPA, Plasmin activation and triggering of the proteolytic cascade involved in Matrigel invasion is blocked by antibodies against uPA (especia lly by anti- A-chain of uPA which interacts with uPAR) and by PA inhibitors such as p-aminobenzamidine which may regulate levels of cell-bound uPA, uP A may also regulate growth in PRCA cells. Indeed, antibodies against uPA A- chain (and also p-aminobenzamidine treatment) interfere with the ATF domain and inhibit cell growth in uPA-producing PC3 and DU145 prostate cancer cel l lines, whereas exogenous uPA (HMW-uPA with ATF) induces growth of LNCaP p rostate tumor cell line. These data support the hypothesis that in prostati c cancer patients at risk of progression, uPA/plasmin blockade may be of th erapeutic value by blocking both growth of the primary tumor and disseminat ion of metastatic cells.