Immunoexpression and Prognostic Significance of TIMP-1 and -2 in Oral Squamous Cell Carcinoma

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are capable of degrading different substrates within the extracellular matrix, and which are believed to be crucial for tumor invasion and metastasis. Tissue inhibitors of MMPs (TIMPs) can inhibit the action of MMPs but also can show a paradoxical poor prognostic effect. In order to evaluate the prognostic significance of TIMPs, we studied the expression of TIMP-1 and -2 in series of 68 oral squamous cell carcinomas (OSCC) by immunohistochemistry. Expression of TIMP-1 was detected in 45 cases (66.2%). In all of these TIMP-1 was expressed in tumoral tissue, and in 19 of them also in the surrounding stroma. In cancer tissue, TIMP-1 was observed in three patterns: homogeneous, central and irregular. Immunoreactivity for TIMP-2 was detected in 38 cases (56%) in tumoral tissue and 9 (13.2%) in the stroma. The expression pattern of TIMP-2 was the same three as TIMP-1 and one more: invasive front of tumoral nests. TIMP-1 expression was not correlated with clinical or pathological parameters. However, TIMP-2 was significantly correlated with T stage (p=0.03), TNM stage (p=0.01), local recurrence (p=0.04), and poor survival (p=0.03, odds ratio=2.75). TIMP-1 and TIMP-2 were significantly correlated with cyclin D1 (p=0.04; p=0.015, respectively) and p53 expressions (p=0.02; p=0.04, respectively). Finally, TIMP-1 but no TIMP-2 was associated with the nuclear antigen Ki-67 (p=0.001). These results suggest that TIMP-1 and -2 are expressed in tumoral and stromal tissue in OSCC. TIMP-2 is related to advanced disease, recurrence and poor prognosis.