Proliferation and malignant transformation of melanocytes.

Over the years, several approaches have been taken to identify genes involved in the malignant transformation of melanocytes. They include (1) identification of recurring karyotypic changes; (2) transfection of mouse fibroblasts (NIH 3T3) with melanoma DNA to identify dominantly acting oncogenes; (3) a search for genes that are expressed in malignant but not normal melanocytes and vice versa; and (4) linkage analysis in melanoma-prone families and animals. Taken together, the results indicate that progression to malignancy involves aberrant unregulated expression of genes acting in signal transmission pathways, such as genes for growth factors, growth factor receptors, and GTP binding proteins. The abnormalities include the loss of certain chromosomes (human) and tissue-specific genes (Xiphophorus hybrids) possessing the ability to suppress tumorigenicity. Constitutively active receptor tyrosine kinases appear to be dominantly acting oncogenes in melanomas of fish and in human melanomas. Inhibition of these kinases by antagonists, antibodies or low molecular weight inhibitors, also inhibits melanoma growth in culture, suggesting new directions in drug design for the management of melanomas.