Serum levels of gelatinases, their inhibitors and neutrophil gelatinase-associated lipocalin: worthwhile non-invasive biomarkers for bladder cancer patients’ management

Recent evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) is required for the development and/or progression of benign and malignant disease, and is overexpressed in several types of tumor. Gelatinase A and B (MMP-2 and -9) by degrading components of the extracellular matrix and thus promoting the release of growth factors, are important in tumor growth and tumorigenicity. Their activity is strictly controlled by the specific tissue inhibitors: TIMP-1 and -2. Disruption of the balance between MMPs and TIMPs is thought to facilitate tumor progression and recurrence. Moreover, MMP-9 enhances its enzymatic activities by binding NGAL and forming the MMP-9/NGAL complex. Therefore, these six molecules have been proposed as soluble biomarkers for numerous malignancy. We measured the concentration of these molecules in the sera of 41 patients with bladder carcinoma using enzyme-linked immunoassay. Sera samples of 53 healthy volunteers were used as controls. In the sera of the control group, MMP-2, TIMP-2, MMP-9/NGAL complex and NGAL were detected in all specimens, whereas MMP-9 and TIMP-1 were undetectable, being at or low the sensitivity of the assay. Vice versa, all the six molecules were detected in the sera from the patients studied and the mean values were higher than that detected in the control group. In particular tumor staged as non muscle invasive (Ta and T1) showed significantly higher NGAL values compared with muscle invasive (>T1) bladder cancer (32.8 ng/ml vs 16.2 ng/ml; p=0.029). The discriminatory ability was confirmed by ROC curve analysis that revealed an AUC of 0.75 with a sensitivity of 0.88 and a specificity of 0.67. These preliminary data suggest that NGAL measurement in sera might provide clinicians additional quantitative and objective information on bladder tumor differentiation.