Molecular mechanisms of melanoma metastasis.
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.
Bar-Eli
M
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Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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
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