The Oncologist-2004-Perlis-182-7

The development of melanoma is associated with the

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Unformatted text preview: velopment of melanoma is associated with the loss of E-cadherin and the appearance of N-cadherin (Fig. 2). Cadherins are cell-surface glycoproteins that promote calcium-dependent cell-cell adhesion, and they are expressed in developmental-, cell-, and tissue-specific manners. The major adhesion mediator between keratinocytes and normal melanocytes is E-cadherin, which disappears during melanoma progression [36]. While normal melanocytes express E-cadherin, this molecule is not found on nevus or melanoma cells [33, 35]. The loss of E-cadherin likely plays a crucial role in tumor progression. Cells that have lost epithelial differentiation, as manifested by the loss of functional E-cadherin, show increased mobility and invasiveness. Keratinocytes can no longer control melanoma cells that have lost E-cadherin. When melanoma cells are forced to express E-cadherin and are cocultured with keratinocytes, they dramatically change: melanomas adhere to keratinocytes, no longer express invasion-related molecules, and lose their invasive capacities [37]. Instead of E-cadherin, melanoma cells express N-cadherin, which allows them to change cellular partners. Melanoma cells adhere through N-cadherin to fibroblasts and endothelial cells. N-cadherin is a survival factor for melanoma cells as they migrate through the dermis [38]. Melanoma cells establish gap junctions with fibroblasts; gap junctions are small channels for electrolyte transport. N-cadherin is also a major adhesion receptor when melanoma cells adhere to each other; coreceptors such as MCAM facilitate cluster formation. Along with the upregulation of N-cadherin and the increased association of melanoma cells with stromal fibroblasts and endothelial cells, occurs a major shift in expression of cell surface receptors on malignant cells. Major changes in expression levels occur for cell-cell and cell-matrix adhesion receptors. One of the most important molecules is the vitronectin receptor αvβ3. It is a multifunctional receptor binding not only vitronectin but over ten other matrix proteins, and 185 it is also involved in cell-cell adhesion [39]. Overexpression of β3 integrin in melanoma cells leads to highly increased invasiveness and tumorigenicity [40]. Signaling through the αvβ3 receptor in melanoma cells occurs through the MAPK proliferation pathway, whereas signaling for the other major Recent Advances in Melanoma Biology adhesion receptor, MCAM or CD146, occurs through the survival AKT pathway [41]. Thus, adhesion receptors cooperate with receptor tyrosine kinases for activation of the major proliferation and survival pathways [42]. Antagonists for the αvβ3 receptor are currently in clinical trials [43]. They Figure 1. Photograph (A) and histologic section (B) depicting UV-light-induced melanocytic lesions in human skin. A) An abdominal human skin graft on a severe combined immunodeficient (SCID) mouse developed this melanocytic lesion following 4 weeks of injections of bFGF/Ad5 (once weekly) and UV-B irradiation (30-50 mJ/cm2, three times each wee...
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