Importance of P-Cadherin, β-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma

Abstract

PURPOSE: It has been proposed that melanoma cells shift from E-cadherin to N-cadherin expression during tumor development, and recent gene profiling has shown increased expression of Wnt5a/Frizzled in aggressive melanomas possibly by interactions with beta-catenin. We therefore wanted to investigate the role of cadherin subtypes, beta-catenin, and Wnt5a/Frizzled in melanocytic tumors, with focus on prognosis in nodular melanomas. EXPERIMENTAL DESIGN: The immunohistochemical expression of E-cadherin, N-cadherin, P-cadherin, beta-catenin, and Wnt5a/Frizzled was examined using tissue microarrays of 312 melanocytic tumors. RESULTS: Cytoplasmic expression of P-cadherin was associated with increasing tumor thickness (P=0.005) and level of invasion (P=0.019), whereas membranous staining was associated with thinner (P=0.012) and more superficial (P=0.018) tumors. Increased cytoplasmic P-cadherin was associated with reduced survival (P=0.047). Lack of nuclear beta-catenin expression was related to increased tumor thickness (P=0.002) and poor patient survival in univariate (P=0.0072) and multivariate (P=0.004) analyses. Membranous expression of N-cadherin was significantly increased from primary tumors to metastatic lesions, whereas E-cadherin staining tended to be decreased. Wnt5a and its receptor Frizzled were highly coexpressed, and nuclear expression of both markers was significantly reduced from benign nevi to melanomas, with a shift from nuclear to cytoplasmic expression in malignant tumors. In addition, Wnt5a expression was significantly associated with nuclear beta-catenin expression. CONCLUSIONS: Alterations in the expression and subcellular localization of cell adhesion markers are important in the development and progression of melanocytic tumors, and strong cytoplasmic P-cadherin expression and loss of nuclear beta-catenin staining were associated with aggressive melanoma behavior and reduced patient survival.