Urinary release of 72 and 92 kDa gelatinases, TIMPs, N-GAL and conventional prognostic factors in urothelial carcinomas

Objectives: A urinary release of gelatinases A and B matrix metalloproteinases-2, -9 (MMP-2, -9), and tissue inhibitors (TIMP-1, -2) occurs during normal epithelial turnover. A proteinase increase, reduced inhibitors or both potentially account for cell mobility and bladder cancer progression. In order to define normal levels and thresholds for transitional cell carcinoma (TCC) patients, urinary gelatinases, tissue inhibitors and neutrophil-gelatinase-associated lipocalin (N-GAL) were investigated for end-point clinical status and compared with normal subjects during a 2-year follow-up prospective study. Methods: Urine specimens [50 adult normal controls; 28 in situ carcinoma patients (pTa) and 23 with ruptured basement membrane (pT1-4)] were screened by gelatin zymograms, immunoblots and ELISA. Results: (1) An important release of inhibitors over low levels of active enzymes was observed in controls independently of age and sex except for higher TIMP-1 levels in males. (2) In cancer patients, increased pro-MMP-9 and active MMP-2 with reduced TIMP-2 levels correlated with higher stages and histological grades. (3) Conversely, reduced MMP-9 and lipocalin levels were initial hallmarks of clinical relapses. Conclusions: The imbalance between increased MMP-2, -9 and decreased TIMP-2 levels appears to be linked to tumor stage and grade and, more importantly, to clinical events. Changes in the MMP-9 activation state and a lack of N-GAL present as novel markers of tumor progression. (C) 2002 Elsevier Science B.V. All rights reserved.