Endothelin receptor B is required for the expansion of melanocyte precursors and malignant melanoma.
Since embryonic development and tumorigenesis share common characteristics, studying the role of genes during development can identify molecules that have similar functions in both processes. C-kit and Endothelin receptor B (EDNRB or ETRB) are crucial for melanocyte development in mice and humans but have different functions. While c-kit is needed for survival throughout development until late stages of differentiation in the skin, EDNRB promotes early expansion and migration while delaying the differentiation of melanocyte precursors. Transformation of normal melanocytes to melanoma cells is often associated with gradual loss of differentiation and the gain of high autonomous capacity to proliferate. In accordance with their different roles, c-kit expression is gradually lost during melanoma transformation, while that of EDNRB is greatly enhanced and can serve as a marker of melanoma progression. Inhibiting EDNRB function with a specific antagonist (BQ788) in human melanoma cell lines results in inhibition of growth often associated with induced differentiation indicating that, during melanoma transformation also, the function of EDNRB is to promote growth. EDNRB function does not seem to be essential in the adult, as BQ788 administration to healthy people does not result in major effects. This is probably why BQ788 can specifically inhibit the growth of xenograft human melanoma tumors in nude mice, in a way resembling spontaneous human melanoma regression and why it could serve as a potential therapeutic agent for melanoma.
Lahav
Ronit
R
Institut Universitaire de Pathologie, Lausanne, Switzerland. ronit.lahav@melcure.com
D000818:Animals; D002454:Cell Differentiation; D065131:Endothelin B Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D006801:Humans; D008544:Melanocytes / Q000166:cytology*; D008545:Melanoma / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology*; D012867:Skin / Q000166:cytology; D019089:Stem Cell Factor / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*
D065131:Endothelin B Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D019089:Stem Cell Factor; C086539:BQ 788; D019009:Proto-Oncogene Proteins c-kit