Halaban R, Moellmann G
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510.
Crit Rev Oncog. 1991;2(4):247-58.
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.
多年来，人们采用了多种方法来鉴定参与黑素细胞恶性转化的基因。这些方法包括：（1）鉴定反复出现的核型变化；（2）用黑色素瘤DNA转染小鼠成纤维细胞（NIH 3T3）以鉴定具有显性作用的癌基因；（3）寻找在恶性黑素细胞而非正常黑素细胞中表达的基因，反之亦然；（4）对易患黑色素瘤的家族和动物进行连锁分析。综合来看，结果表明向恶性肿瘤的进展涉及信号传导途径中起作用的基因的异常失控表达，例如生长因子、生长因子受体和GTP结合蛋白的基因。这些异常包括某些具有抑制肿瘤发生能力的染色体（人类）和组织特异性基因（剑尾鱼杂交种）的缺失。组成型活性受体酪氨酸激酶似乎是鱼类黑色素瘤和人类黑色素瘤中具有显性作用的癌基因。用拮抗剂、抗体或低分子量抑制剂抑制这些激酶，也能抑制培养中的黑色素瘤生长，这为黑色素瘤治疗的药物设计指明了新方向。
