Importance of P-cadherin, β-catenin, and Wnt5a/Frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma

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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 β-catenin. We therefore wanted to investigate the role of cadherin subtypes, β-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, β-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 β-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 β-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 β-catenin staining were associated with aggressive melanoma behavior and reduced patient survival. © 2005 American Association for Cancer Research.

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Bachmann, I. M., Straume, O., Puntervoll, H. E., Kalvenes, M. B., & Akslen, L. A. (2005). Importance of P-cadherin, β-catenin, and Wnt5a/Frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clinical Cancer Research, 11(24), 8606–8614. https://doi.org/10.1158/1078-0432.CCR-05-0011

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