Lessons from melanocyte development for understanding the biological events in naevus and melanoma formation

Recent advances in mouse genetics have identified molecular changes that ar e critical for melanocyte maturation and differentiation. This review brief ly summarizes the current knowledge of distinct steps in melanocyte develop ment, and identifies for each step the most important molecules such as the growth factors stem cell factor and endothelin-3, with their respective re ceptors. Classical cadherins, i.e. E-cadherin, N-cadherin and P-cadherin, d etermine melanocyte positioning in the skin. During naevus and melanoma dev elopment, the two growth factor signalling pathways are downregulated, wher eas cadherin expression shifts concomitantly with re-positioning of the nae vus and melanoma cells in the skin. Loss of E-cadherin and gain of N-cadher in by melanoma cells has profound consequences for the regulatory cross-tal k between various types of cells in the skin. Naevus and melanoma cells tha t do not express E-cadherin are resistant to control by keratinocytes and e stablish close communications with fibroblasts and endothelial cells. Howev er, forced expression of E-cadherin in melanoma cells can reverse the malig nant phenotype by re-establishing the control of keratinocytes over the mel anoma cells. Even highly aggressive metastatic melanoma cells can be signal led to turn off the expression of genes associated with tumour invasion and metastasis, suggesting that this strategy could be utilized in the therapy of melanoma. (C) 2000 Lippincott Williams & Wilkins.