Clinical relevance of neutral endopeptidase overexpression in melanoma

Abstract

8028 Background: Neutral Endopeptidase (NEP/CD10) is a cell surface peptidase expressed in a variety of normal and neoplastic tissue. Both loss of and overexpression of NEP have been reported in different types of tumors. Defining the role of NEP in the clinical progression of melanoma is particularly relevant given the availability of NEP inhibitors. Our aim was to determine if NEP expression correlated with clinicopathological parameters and survival. We also investigated the upregulation of NEP transcription as a possible mechanism of NEP overexpression. Methods: Eighty-four patients who were prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group database at the New York University School of Medicine were studied. Ninety-three specimens from the 84 patients were examined for NEP protein expression using an immunohistochemical assay, including 33 primary melanoma (thickness <1mm, N=15; 1–4mm, N=15; >4mm, N=3) and 60 metastatic melanoma specimens. NEP overexpression was defined as either moderate or diffuse. NEP transcript expression was assessed using Affymetrix U133Plus2.0 GeneChips in 37 metastatic melanoma cases. NEP transcript upregulation was defined as >2 fold increase compared to NEP transcript expression in normal lymph node tissue. Results: A statistically significant difference was observed between NEP overexpression in primary [1/33 (3%)] versus metastatic disease [18/60 (30%)] (Fisher’s exact test, p=0.002). In addition, there was a statistically observed association between NEP transcript upregulation and NEP protein overexpression (p=0.002). Among patients with metastatic disease, median survival time was shorter for patients who overexpressed NEP compared to those who had normal NEP expression (10.2 yrs. versus 12.7 yrs., respectively); however this difference was not statistically significant (p=0.74 by log-rank test). Conclusions: Our data support a role for increased NEP expression in the progression of melanoma to metastatic disease. Functional studies are needed to better understand the role of NEP upregulation in melanoma pathogenesis and progression and to determine if there is a role for NEP inhibitors in the treatment of melanoma. No significant financial relationships to disclose.