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

被引:142
作者
Bachmann, IM [1 ]
Straume, O [1 ]
Puntervoll, HE [1 ]
Kalvenes, MB [1 ]
Akslen, LA [1 ]
机构
[1] Univ Bergen, Gade Inst, Sect Pathol, N-5020 Bergen, Norway
关键词
D O I
10.1158/1078-0432.CCR-05-0011
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, andWnt5a/Frizzled was examined using tissue microarrays of 312 melanocytic tumors. Results: Cytoplasmic expression of E-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 p-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 p-catenin staining were associated with aggressive melanoma behavior and reduced patient survival.
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页码:8606 / 8614
页数:9
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