title: Molecular mechanisms of melanoma metastasis.
abstract: The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not very well defined. Expression of the tyrosine-kinase receptor c-KIT progressively decreases during local tumor growth and invasion of human melanomas. To provide direct evidence that c-KIT plays a role in metastasis of human melanoma, we transfected the c-KIT gene into c-KIT-negative, highly metastatic human melanoma cells and subsequently analyzed their tumorigenic and metastatic potential in nude mice. Enforced c-KIT expression significantly inhibited tumor growth and metastasis. Exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. These results suggest that the loss of c-KIT receptor may allow malignant melanoma cells to escape SCF/c-KIT-mediated apoptosis, thus contributing to tumor growth and eventually metastasis. The expression of c-KIT and other genes associated with malignant melanoma (such as MCAM/MUC18) is highly regulated by the transcription factor AP-2. The AP-2 protein is not expressed in malignant melanoma cells. Therefore, loss of AP-2 expression might be a crucial event in the progression of human melanoma.
authors.affiliation: Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bar-Eli
mesh_terms: D000818:Animals; D015703:Antigens, CD; D051929:CD146 Antigen; D004268:DNA-Binding Proteins / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000503:physiopathology / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019006:Neural Cell Adhesion Molecules; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D051929:CD146 Antigen; D004268:DNA-Binding Proteins; C497902:MCAM protein, human; C497903:Mcam protein, mouse; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit