[Frontiers in Bioscience 3, d1005-1010, September 15, 1998]
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MOLECULAR EVENTS IN MELANOMA DEVELOPMENT AND PROGRESSION

Friedegund Meier1, Kapaettu Satyamoorthy1, Mark Nesbit1, Mei-Yu Hsu1, Birgit Schittek2, Claus Garbe2, and Meenhard Herlyn1

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 191041, Department of Dermatology, University of Tuebingen, Liebermeisterstr.25, 72076 Tuebingen, Germany2

Received 7/17/98 Accepted 8/10/98

5. ADHESION MOLECULES IN MELANOMA DEVELOPMENT AND PROGRESSION

Expression of a given adhesion molecule on melanocytes from different stages of tumor progression is a dynamic process. There is upregulation of Mel-CAM/MUC18, chondroitin sulfate proteoglycan (CSPG), gangliosides GD3 and acetylated GD3 during the transition from normal melanocytes to nevi (figure 4). Our laboratory has defined Mel-CAM/MUC18 as an adhesion receptor that is involved in cell-cell interactions (18). Its expression is upregulated in a step-wise fashion (figure 4) and coincides with the separation of nevus cells from keratinocytes (18).

Figure 4. Dynamic changes in expression of adhesion receptors and ECM proteins in melanoma progression. Decreased expression (downward arrow) is seen for some cadherins, CAMs, integrins and ECM proteins and is relatively uncommon. A strong increase (upward arrow) of a variety adhesion-related molecules, first in nevi, then in VGP primary melanomas, is more common. Parentheses indicate molecules exhibiting a gradual increase between steps.

Mel-CAM binds to an as yet unidentified ligand (19), and may play a major role in metastasis by mediating not only melanoma-melanoma cell interactions (figure 5), but also melanoma-endothelial cell adhesion (figure 6). Mel-CAM/MUC18 appears to act in concert with alphavbeta3, the vitronectin receptor, in promoting metastasis. As the cells progress from RGP to VGP, expression of alphavbeta3, alpha2beta1, alpha3beta1, alpha4beta1, ICAM-1, and GD2 ganglioside is increased. However, the most notable marker is the beta3 subunit of alphavbeta3 integrin. In our hands, alphavbeta3 is the most specific melanoma-associated marker that distinguishes RGP from VGP melanomas (figure 4) (20). It is also a prime candidate for prognostic studies (21). In addition, a decrease in adhesion molecule expression with melanoma progression has been described. The most notable example is E-cadherin which is found on normal melanocytes, to a lesser degree on nevi and little on melanomas (10). The loss of E-cadherin expression has significant biological consequences in melanocytic cells. Forced reexpression of E-cadherin in melanoma cells leads to growth retardation, inhibition of invasion and induction of apoptotic death in a three-dimensional skin reconstruct, and decreased tumorigenicity in mice (22). Thus, E-cadherin may act as a tumor suppressor in the melanoma system.

Figure 5. Adhesion receptors in melanoma-melanoma cell interactions. The dominant adhesion systems appears to be Mel-CAM and its unidentified ligand. Vitronectin receptor-mediated adhesion may require prior activation. The functional significance of CD44 and its different isoforms in melanoma adhesion remains unclear.

Figure 6. Adhesion receptors in melanoma-endothelial cell interactions. Melanoma cells adhere to endothelial cells apparently in a sequence of steps, starting with Mel-CAM/ligand, followed by integrin-mediated adhesion since proper activation is required for the latter.