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

Authors' Affiliation: The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway

Requests for reprints: Lars A. Akslen, Children's Hospital, Harvard Medical School, Vascular Biology Program, Karp Family Research Labs 12.125, 300 Longwood Avenue, Boston, MA 02115-5737. Phone: 617-919-2426; Fax: 617-739-5891; E-mail: lars.akslen{at}childrens.harvard.edu or lars.akslen{at}gades.uib.no.

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 ß-catenin. We therefore wanted to investigate the role of cadherin subtypes, ß-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, ß-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 ß-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 ß-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 ß-catenin staining were associated with aggressive melanoma behavior and reduced patient survival.

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