Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma

Abstract

Background: Urokinase plasminogen activator (u-PA) plays a key role in the metastatic process by promoting plasmin mediated tissue degradation. 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 factors such as the TNM staging, histologic grading, ploidy, and the clinical outcome of the patients.

Methods: One hundred fifty-two patients who underwent transperitoneal tumor nephrectomy for RCC were followed 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 from detergent extracted tissue samples (1% Trinton-X-100 in triethanolamine-buffered saline) and measured with an enzyme-linked immunoadsorbent assay.

Results: PAI-1 significantly correlated with the prevalence of distant metastasis (M0: 10.04 vs. M1 23.79, P=0.02) and the development of new metastasis postoperatively (M0: 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 patients 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 development 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 metastasizing (u-PA > 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 relapse 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 with PAI-1, a high and low risk group for disease free survival can be discriminated.