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P-Cadherin Promotes Cell-Cell Adhesion and Counteracts Invasion in Human Melanoma

Laboratory of Experimental Cancerology, Departments of ¹ Radiotherapy and Nuclear Medicine, ² Dermatology, and ³ Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital and ⁴ Units of Molecular Cell Biology and Molecular and Cellular Oncology, Department of Molecular Biomedical Research, VIB-Ghent University, Ghent, Belgium and ⁵ Institute of Pathology and Molecular Immunology of Porto University, Porto, Portugal

Requests for reprints: Marc Bracke, Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, 1P7, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Phone: 3292403007; Fax: 3292404991; E-mail: brackemarc{at}hotmail.com.

Malignant transformation of melanocytes frequently coincides with alterations in epithelial cadherin (E-cadherin) expression, switching on of neural cadherin (N-cadherin), and, when progressed to a metastatic stage, loss of membranous placental cadherin (P-cadherin). In vitro studies of melanoma cell lines have shown invasion suppressor and promoter roles for E-cadherin and N-cadherin, respectively. In the present study, we investigated the effect of P-cadherin on aggregation and invasion using melanoma cells retrovirally transduced with human P-cadherin. De novo expression of P-cadherin in P-cadherin–negative cell lines (BLM and HMB2) promoted cell-cell contacts and Ca²⁺-dependent cell-cell aggregation in two- and three-dimensional cultures, whereas it counteracted invasion. These effects were not observed following P-cadherin transduction of endogenously P-cadherin–positive MeWo cells. In addition, P-cadherin–transduced BLM cells coaggregated with keratinocytes and showed markedly reduced invasion in a reconstructed skin model. The proadhesive and anti-invasive effects of P-cadherin were abolished on targeted mutation of its intracellular juxtamembrane domain or its extracellular domain. For the latter mutation, we mimicked a known missense mutation in P-cadherin (R503H), which is associated with congenital hypotrichosis with juvenile macular dystrophy.

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