This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bachmann, I. M. Articles by Akslen, L. A. Search for Related Content PubMed PubMed Citation Articles by Bachmann, I. M. Articles by Akslen, L. A.

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.

This article has been cited by other articles:

				G. M. Kreizenbeck, A. J. Berger, A. Subtil, D. L. Rimm, and B. E. Gould Rothberg Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 949 - 958. [Abstract] [Full Text] [PDF]

				T. F. Gajewski, E. A. Grimm, B. J. Nickoloff, and A. T. Weeraratna New Potential Therapeutic Targets in Melanoma ASCO Educational Book, January 1, 2008; 2008(1): 404 - 407. [Abstract] [Full Text] [PDF]

				K. Gravdal, O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer Clin. Cancer Res., December 1, 2007; 13(23): 7003 - 7011. [Abstract] [Full Text] [PDF]

				K. D. McCall, N. Harii, C. J. Lewis, R. Malgor, W. Bae Kim, M. Saji, A. D. Kohn, R. T. Moon, and L. D. Kohn High Basal Levels of Functional Toll-Like Receptor 3 (TLR3) and Noncanonical Wnt5a Are Expressed in Papillary Thyroid Cancer and Are Coordinately Decreased by Phenylmethimazole Together with Cell Proliferation and Migration Endocrinology, September 1, 2007; 148(9): 4226 - 4237. [Abstract] [Full Text] [PDF]