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


METHODS
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.
Bachmann
Ingeborg M
IM
The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway.
Straume
Oddbjørn
O
Puntervoll
Hanne E
HE
Kalvenes
May Britt
MB
Akslen
Lars A
LA
D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D015820:Cadherins / Q000032:analysis / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D051157:Frizzled Receptors; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000175:diagnosis / Q000401:mortality* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000473:pathology; D009506:Nevus / Q000175:diagnosis / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000032:analysis / Q000378:metabolism; D012878:Skin Neoplasms / Q000175:diagnosis / Q000401:mortality* / Q000473:pathology; D015854:Up-Regulation; D051153:Wnt Proteins / Q000032:analysis / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
D014408:Biomarkers, Tumor; D015820:Cadherins; C498589:FZD5 protein, human; D051157:Frizzled Receptors; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin