Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma

Tumour cell invasion and metastasis is a multistep process that involves th e degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative re gulators of MMPs and thus prevent tumour cell invasion and metastasis by pr eserving extracellular matrix (ECM) integrity. In the present study we exam ined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour sp ecimens and two thyroid carcinoma cell lines (NPA and SW579). We also inves tigated the effect of high TIMP-1 expression on the invasive potential of N PA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcrip ts was found in stages III and IV vs benign goitre (P < 0.0001). However, T IMP-1 expression was not increased in NPA and SW579 cells, both of which ar e derived from poorly differentiated thyroid tumours. Immunohistochemical s tudy showed strong TIMP-1 staining in the stroma cells of advanced stages o f carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a signi ficant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of T IMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyro id tumour invasion/metastasis suppressor.