Paradox of ras Oncogenes in Malignant Melanoma

Abstract

Our studies over the past several years have concentrated on the role of oncogenes in the pathogenesis of malignant melanoma. Our objectives have been i) to determine the status of oncogene and proto‐oncogene activation and expression during specific clinically defined stages of melanoma; ii) to determine if these genes are involved in the induction, maintenance, and/or metastatic potential of melanoma cells; iii) to decipher the relationship of neoplastic transformation to differentiation in this disease; and iv) to determine the nature and timing of specific events which disrupt the normal functioning of the melanocyte. The experiments are intended to test the concept that multiple, cooperating, independently activated oncogenes are involved in the evolution of malignant melanoma. The range of data we have accumulated to date suggests a definite, but complex, role for oncogenes in the development of melanoma and points to a probable interrelatedness of melanocyte‐melanoma cellular differentiation programs and the process of malignant transformation. Further, our research has detailed a specific sequence of transformation‐related biological and biochemical events occurring in vitro in the human melanocyte in response to ras oncogenes, and has generated information suggesting the presence of, as yet, undefined genetic elements in melanoma.Our work has evolved along a broad front, and we have analyzed the status of a large series of oncogenes in a range of melanomas and related tissues. However, in this brief review we will limit our focus to the ras gene family and discuss the data from my group and others which suggests not only a complex role for ras oncogenes in the etiology of melanoma but also a paradoxical one.