Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study.

Abstract

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes implicated in the invasion and metastasis of many kinds of cancer because of their ability to degrade components of extracellular matrix. Specific tissue inhibitors of matrix metalloproteinases (TIMPs) regulate their activity. MMPs and TIMPs were identified in many neoplasm, including cancers of head and neck, lung, breast and colon cancer. In most researches a strong relation between MMPs and TIMPs expression and a clinical course of disease was observed, although there were many discrepancies between the authors. The aim of this research was to evaluate the expression of MMP1, MMP2, MMP9 and TIMP1, TIMP2, TIMP3 in head and neck cancer and to investigate the prognostic impact of these factors in patients with these tumors. 210 patients with head and neck cancer that underwent surgical treatment with at least a 5-year follow-up were included in the study. Immunohistochemical studies were performed on formalin fixed, paraffin embedded sections by using monoclonal antibodies against MMP1, MMP2, MMP9 and TIMP1, TIMP2, TIMP3 antigens and Dako EnVision detection system. For all of the markers diffusion, cytoplasmatic staining of tumor cells and some surrounding stromal cells was observed. There was a correlation between TIMP2 and TIMP3 overexpression and tumors staged as III/IV (p=0,037 and p=0,022, respectively). Also, we observed a strong association between MMP2 expression and the presence of nodal metastases (p=0,013). It was found that the TIMP2 overexpression was significantly more frequent in the tumors of patients facing nodal recurrences during the follow-up period (p=0,05). Positive immunostainings of MMP1, MMP2, MMP9 and TIMP1, TIMP2 were significantly related to the higher tumor grade (G3). Specially strong correlation was seen between high TIMP2 expression and low histological differentiation (G3) (p<0,001). In univariate analysis the overall survival rate was shorter in cases with positive MMP2 and/or MMP9 expression. Patients with TIMP2 positive expression diminished both overall and disease-free survival (p=0,049). In multivariate analysis positive TIMP2 and MMP2 expressions were independent prognostic factors for overall survival. Only advanced nodal metastatic tumors (N3) were related to disease free survival. Our data suggest the conclusion that imbalance between matrix metalloproteinases and their inhibitors play the important role in progression of head and neck cancer and patients' prognosis.