Association of TIMP3 expression with vessel density, macrophage infiltration and prognosis in human malignant melanoma. (January 2016)

• Record Type: Journal Article
• Authors: Das, Asha M.; Koljenović, Senada; Oude Ophuis, Charlotte M.C.; van der Klok, Thom; Galjart, Boris; Nigg, Alex L.; van Cappellen, Wiggert A.; Noordhoek Hegt, Vincent; Dinjens, Winand N.M.; Atmodimedjo, Peggy N.; Vermeulen, Cindy E.; Verhoef, Cornelis; Eggermont, Alexander M.M.; ten Hagen, Timo L.M.
• Is Part Of: European journal of cancer. Volume 53(2016)
• Page Start: 135
• Page End: 143
• Publication Date: 2016-01
• Subjects: TIMP3 -- Melanoma -- Angiogenesis -- Macrophage infiltration -- Promoter methylation; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.09.014
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Aims: Several anti-tumour properties have been ascribed to the tissue inhibitor of matrix metalloproteinases-3 (TIMP3) gene, including inhibition of neovascularisation in tumour xenografts. Reduced protein expression has been linked to promoter hypermethylation and allelic loss of heterozygosity in various human malignancies. In melanoma-positive lymph nodes from patients, we evaluated the association between TIMP3 expression, vessel density, macrophage infiltration and potential correlations with disease-free survival (DFS) and overall survival (OS). Patients and methods: TIMP3 expression was analysed by immunohistochemistry (IHC) in melanoma lymph node biopsies of stage III melanoma patients (n = 43). Blood vessel density and macrophage infiltration were quantitatively assessed and correlation with TIMP3 expression was investigated. Methylation status of the gene promoter was determined using methylation-specific polymerase chain reaction (MSP). Protein expression and promoter methylation status were investigated for associations with DFS and OS. Results: Reduced expression of TIMP3, as determined by IHC, was observed in 74% of the cases (32 in 43). A significant inverse correlation was observed between TIMP3 expression and vessel density (p = 0.031). Correlation between TIMP3 expression and macrophage infiltration was not statistically significant (p = 0.369). MSP analysis revealed methylation of the gene promoter in 18% (7 in 38) of the analysed cases. No differences in OS and DFS were observed between cases with high and low TIMP3 expression. Gene promoter methylation was significantly associated with both poor 5-year DFS (p = 0.024) and OS (p = 0.034). Conclusions: Our data indicate that TIMP3 is a dominant negative regulator of angiogenesis in cutaneous melanoma and gene silencing by promoter methylation is associated with poor outcome. Highlights: Tissue inhibitor of matrix metalloproteinases-3 (TIMP3) expression in stage III melanoma lymph nodes was evaluated by immunohistochemistry. Reduced protein expression was observed in a majority of cases. TIMP3 protein expression was inversely correlated with vessel density. Gene promoter methylation was detected in 18% of cases and impacted outcome. TIMP3 is a negative regulator of angiogenesis in melanoma.