Reduced tissue inhibitor of metalloproteinase-2 expression is associated with advanced medullary thyroid carcinoma

Abstract

Matrix metalloproteinases (MMPs) are enzymes for extracellular matrix remodeling that are involved in tumor growth, progression and metastasis. Among them, MMP-9 has been implicated in tumor angiogenesis. Tissue inhibitor of matrix metalloproteinase (TIMP)-2, a member of the family of MMP inhibitors, induces apoptosis and inhibits various stages of angiogenesis. Previous studies analyzing the expression of MMP-9 and TIMP-2 in medullary thyroid carcinoma (MTC) are scarce. The aims of the current study were to evaluate MMP-9 and TIMP-2 expression in MTC samples and correlate the results with clinical parameters. Paraffin-embedded samples from 77 MTC patients were evaluated for expression by immunohistochemistry. The clinical data in medical records were retrospectively reviewed. In total, 77 patients aged 35.6±17.1 years were enrolled. Of these patients, 36 had hereditary disease (46.8%). Immunohistochemical staining for MMP-9 and TIMP-2 was detected in 89.6 and 93.5% of the samples, respectively. The expression of MMP-9 was not found to correlate with clinical parameters, although, a trend toward a correlation between MMP-9 and distant metastasis was observed (P=0.053). By contrast, TIMP-2 staining was found to correlate with age at diagnosis (P=0.026) and negatively correlate with tumor size and tumoral stage (P=0.002 and P=0.001, respectively). Notably, the highest levels of TIMP-2 expression were observed in patients with intrathyroidal disease. The MMP-9 enzyme involved in extracellular matrix remodeling is overexpressed in MTC lesions and may contribute to tumor vascularization and growth. Reduced levels of TIMP-2 expression may be implicated in tumor progression and spread of disease.