Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.
The malignant phenotype of prostatic tumor cells correlates with the expression of both uPA and its cell-membrane receptor (uPAR); however, there is little information concerning the role of cell-bound uPA in matrix degradation and invasion. Our results suggest that cell-associated uPA plays a key role in regulating the amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differential production of uPA corresponds with the capacity to bind and activate plasminogen. In addition, we provide 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 activity. LNCaP cells (which do not produce uPA but express uPAR) may activate plasmin through exogenous uPA. In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observed in several other systems. PAI-1 accumulation in the conditioned medium (CM) limits plasmin action to the pericellular microenvironment. Our results indicate that MMP-9 and MMP-2 are also activated by plasmin generated by cell-bound but not by soluble, extracellular uPA. Plasmin activation and triggering of the proteolytic cascade involved in Matrigel invasion is blocked by antibodies against uPA (especially 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. uPA 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 cell lines, whereas exogenous uPA (HMW-uPA with ATF) induces growth of LNCaP prostate tumor cell line. These data support the hypothesis that in prostatic cancer patients at risk of progression, uPA/plasmin blockade may be of therapeutic value by blocking both growth of the primary tumor and dissemination of metastatic cells.
Festuccia
C
C
Department of Experimental Medicine, University of L'Aquila, Italy.
Dolo
V
V
Guerra
F
F
Violini
S
S
Muzi
P
P
Pavan
A
A
Bologna
M
M
D001550:Benzamidines / Q000494:pharmacology; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010958:Plasminogen / Q000008:administration & dosage / Q000378:metabolism; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001550:Benzamidines; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D015842:Serine Proteinase Inhibitors; C059485:matrigel; C006500:4-aminobenzamidine; D010958:Plasminogen; D003094:Collagen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases