Matrix metalloproteinases 2, 7, 8, 9 and their type 1 tissue inhibitor in serum of renal cancer patients: clinical and pathologic correlations

Background: The cause of late diagnosis of renal cancer lies in its durable, almost asymptomatic course. Due to the use of antiangiogenic therapies much progress has been made in its treatment in recent years. Yet, many questions concerning the diagnosis, prognosis and prediction of the efficiency of targeted therapy remain unsolved. Therefore, exploration of new renal cancer molecular markers, especially those related to its angiogenic and invasive activities, are still on the agenda. Such markers include the family of matrix metalloproteinases (MMPs) that degrade the majority of extracellular matrix components and are involved at all stages of tumor progression. Aim: Comparative evaluation of MMP2, 7, 8, 9 and type 1 tissue inhibitor (TIMP-1) levels in serum of healthy individuals and patients with renal cancer or benign renal tumors, analysis of their associations with the main clinical and pathologic characteristics of the disease. Materials and methods: We examined 99  renal cancer patients (of those 94 with primary tumor and 5 at progression) and 10 patients with benign renal tumors. The control group included 97 healthy individuals. Levels of the proteins studied were measured using respective direct ELISA kits (Quantikine^®, R&D Systems, USA). Results: MMP-7, MMP-8 and TIMP-1 levels in the sera of renal cancer patients were significantly higher than in the control group and in benign renal tumor patients. MMP-2 and MMP-9 levels did not differ significantly between the study and control groups. At MMP-7 cut-off level of 3.0  ng/mL, its diagnostic sensitivity for primary renal cancer was 84%, specificity in relation to “healthy” control – 87.5%, in relation to the pathologic control (healthy donors+benign renal tumor patients) – 73%. The best sensitivity: specificity ratio for TIMP-1 was 67 and 65% at the cut-off level of 315 ng/ml. No cut-off value with acceptable sensitivity: specificity ratio was found for MMP-8. Serum levels of all these 3 markers were positively associated with disease stage and TNM indices; MMP-7 and TIMP-1 levels also increased with lower differentiation grade. In 5 patients evaluated at disease progression the levels of all the markers studied were markedly higher than in the primary patients, and exceeded the estimated cut-off values. Conclusion: MMP-7 should be regarded as the most promising serological renal cancer marker; its serum levels exceed the cut-off value even in 84% stage I patients. TIMP-1 has acceptable sensitivity (70% and above) only from stage II renal cancer onwards, while MMP-8 levels are increased only at stage III–IV of the disease.