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C. X. Qian, B. F. Fernandes, C. M. Martins, P. Logan, S. Bakalian, M. N. Burnier, Jr.; Expression of Timp-3 in Uveal Melanoma and Its Correlation With Outcome. Invest. Ophthalmol. Vis. Sci. 2008;49(13):59.
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Invasion and metastatic disease are major impediments to the effective treatment of uveal melanoma (UM). Tissue inhibitors of metalloproteinases (TIMPs) negatively regulate matrix metalloproteinases and their local balance is thought to be crucial in the control of UM progression and metastasis. Since TIMP-3 has anti-angiogenic tumor suppressor properties in vitro, the goal of this study was to correlate TIMP-3 expression with known clinical and histopathological parameters of prognosis in UM.
Thirty-nine specimens of paraffin-embedded human uveal melanoma (UM) and controls from breast cancer specimens were immuno-stained with a TIMP-3 antibody using the Ventana BenchMark fully automated machine. The immuno-staining was evaluated in a semi-quantitative method based on the extent and intensity of staining. Clinical-pathological data were obtained, including age, gender, tumor cell type, largest tumor dimension, location of the ocular tumor and treatment modality. The relationship between the clinical-pathological data and the expression of TIMP-3 was evaluated. Moreover, the survival rates of the patients were also assessed using a Kaplan-Meier test.
All 39 specimens stained positive for TIMP-3, of which 15 had a strong expression (38%). Increased expression in TIMP-3 was associated with previous conservative treatment (radiotherapy or thermotherapy) (p=0.04) and epithelioid cell type (p=0.03). In addition, higher TIMP-3 expression was also associated with posterior localization of the tumor and a higher risk of metastasis, although statistical relevance was not reached (p>0.05). Largest tumor diameter showed no correlation with TIMP-3 expression level.
To the best of our knowledge, this is the first report demonstrating that TIMP-3 expression correlates with poor prognostic factors in UM. TIMP-3 overexpression has already been correlated with aggressive behavior and poor prognosis in gastric cancer, lung extracutaneous small cell carcinoma and Merkel cell carcinoma of the skin. It is believed that a balance of TIMP-3 expression in the tumor and surrounding host tissue and stroma is necessary for tumor invasion. Our results warrant further studies to elucidate the mechanism by which TIMPs regulate tumor invasion.
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