CLINICAL RELEVANCE OF UROKINASE PLASMINOGEN-ACTIVATOR, ITS RECEPTOR, AND ITS INHIBITOR IN PATIENTS WITH RENAL-CELL CARCINOMA

BACKGROUND. Urokinase plasminogen activator (u-PA) plays a key role in the metastatic process by promoting plasmin mediated tissue degradati on. Metastatic cell invasion requires localized proteolysis, which may be directed by u-PA receptor. The binding of u-PA and PAI-1 to the u- PA-receptor may cause internalization of the trimeric complex into the cell and activate a tyrosine-kinase. In a prospective study the u-PA, u-PA-R, and PAI-1 content in patients with renal cell carcinoma (RCC) and benign renal tissue were correlated with traditional prognostic f actors such as the TNM staging, histologic grading, ploidy, and the cl inical outcome of the patients. METHODS. One hundred fifty-two patient s who underwent transperitoneal tumor nephrectomy for RCC were followe d up for a mean of 23.9 months. u-PA, u-PA-R, and PAI-1 from the tumor tissue and corresponding benign renal tissue were quantified hom dete rgent extracted tissue samples (1% Trinton-X-100 in triethanolamine-bu ffered saline) and measured with an enzyme-linked immunoadsorbent assa y.RESULTS, PAI-1 significantly correlated with the prevalence of dista nt metastasis (MO: 10.04 vs. M1 23.79, P = 0.02) and the development o f new metastases postoperatively (MO: 10.85 vs. M1 27.36, P = 0.001). A cut-off level of 12 ng/mg protein for PAI-1 selected a group of pati ents at high risk for relapse. Forty-one patients had PAI-1 > 12 ng/mg with 6 relapses compared with 55 patients with PAI-1 < 12 ng/mg with 1 relapse during the follow-up. Content of mu-PA correlated with the d evelopment of distant metastases (log rank 4.32, P = 0.037). A cut-off value of 0.84 ng/mg selected 2 groups: a group at high risk for metas tasizing (u-PA 1 0.84, n = 11 with 9 events and a group at low risk (u -PA < 0.84 with 94 patients and 5 events). Applying a cut-off value of 0.85 for u-PA-R 2 groups could be discriminated: 31 patients had no r elapse with u-PA-R < 0.85 and 18 had 3 recurrences with u-PA-R > 0.85 g/ml. CONCLUSIONS. u-PA, u-PA-R, and PAI-1 are strong and independent prognostic factors for predicting early relapse for RCC. Especially wi th PAI-1, a high and low risk group for disease free survival can be d iscriminated. (C) 1996 American Cancer Society.