[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

6. GROWTH FACTORS, CYTOKINES AND THEIR RECEPTORS IN MELANOMA DEVELOPMENT AND PROGRESSION

Melanoma cells express a variety of growth factors and cytokines (figure 7) and their receptors (figure 8) (11). For several years, we have delineated their functions and have distinguished between autocrine growth factors, those involved in stroma induction (including angiogenesis), and those interacting with the host defense system [i.e., with specific T cells and non-specific inflammatory cells (23, 24)]. In a series of experiments, we have evaluated the role of these molecules in angiogenesis, matrix induction, and monocyte and granulocyte attraction (25-27). Growth factors and cytokines are also suitable as progression markers (figure 9). Tumor cells produce growth factors not only for autocrine growth stimulation, but also for paracrine stimulation of the stromal cells (figure 10). Fibroblasts are activated by melanoma-derived PDGF, whereas endothelial cells are activated by VEGF.

Figure 7. Growth factors and cytokines expressed by melanoma cells. Unlike normal melanocytes, melanoma cells express most of the ligands constitutively, i.e., without prior stimulation. Differences in expression between melanoma cells in culture and in situ are only marginal. However, expression in situ may be more heterogeneous. Individual cell lines or specimens may express several but not necessarily all factors listed.

Figure 8. Growth factor receptors expressed by melanoma cells. Melanoma cells express receptors at levels from a few hundred sites (MSH-R), to ten-thousand (EGF-R) or hundred-thousand (NGF-R) per cell.

Figure 9. Dynamics of growth factor and cytokine expression during progression. bFGF and IL-8 are apparently upregulated early in progression, but IL-8 decreases in metastases. Other factors show an increase particularly at the transition from RGP to VGP melanoma.

Figure 10. Hypothetical tumor-stroma interactions. Melanoma cells produce bFGF for autocrine growth stimulation. Melanoma-derived PDGF and VEGF activate fibroblasts and stimulate angiogenesis, respectively. The activated stromal cells then provide feedback to the tumor cells by producing their own growth factors.