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Tissue Inhibitor of Metalloproteinase-2 as a Multifunctional Molecule of Which the Expression Is Associated with Adverse Prognosis of Patients with Urothelial Bladder Carcinomas

Departments of Pathology [H. G., L. N., I. M., E. G. P., I. T.] and Urology [A. S., C. S., A. G.], Medical School, The National and Kapodistrian University of Athens, Athens 11527, Greece

Purpose: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase (MMP) activity controlling the breakdown of extracellular matrix components and, thus, play an important role in the process of invasion and metastasis. Moreover, there are several new functions, growth control, apoptosis, and angiogenesis-, in which TIMPs seem to be involved. The aim of this study was to elucidate the role of TIMP-2 in human urothelial cancer assessing TIMP-2 protein expression in 106 urothelial bladder carcinomas and evaluating its importance relative to clinicopathologic parameters (age, gender, histological grade, and stage) and patient survival, as well as to markers associated with cell growth and apoptosis (Ki-67, p53, and bcl-2).

Experimental Design: Immunohistochemistry (avidin-biotin complex method-horseradish peroxidase) was performed to detect TIMP-2, Ki-67, p53, and bcl-2 proteins using monoclonal and polyclonal antibodies. Statistical analysis was univariate and multivariate.

Results: TIMP-2 immunohistochemical expression was observed in stromal fibroblasts and in cancerous cells in 26.4% and 69.8% of cases, respectively. TIMP-2 stromal but not cancerous cell expression associated significantly with the high histological grade of carcinomas (P < 0.0001) and the advanced stage of the disease (P = 0.001). TIMP-2 either stromal or cancerous cell expression correlated significantly with the expression of Ki-67 proliferation indice (P = 0.02 and P = 0.044, respectively) and the mutant p53 protein (P = 0.043 and P = 0.045, respectively). In univariate survival analysis patients with positive TIMP-2 stromal cell immunohistochemical expression had a significantly worse overall survival in comparison with TIMP-2 stromal cell-negative patients (log rank test: P = 0.0002). However, in multivariate survival analysis the only independent survival factors were the stage of the disease and patient age.

Conclusions: TIMP-2 protein expression in either the stromal or cancerous cells is associated with the proliferation index Ki-67 and the apoptosis-related protein p53. These findings are in keeping with in vitro studies reporting a growth-promoting ability of TIMP-2 and its involvement in apoptosis regulation. On the other hand, TIMP-2 stromal cell expression only was associated with adverse prognosis of urothelial bladder cancer patients.

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