Molecular changes in human melanoma metastasis.
The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not well defined. Our recent studies have demonstrated that the two tumor suppressor genes, p53 and p16/CDKN2, do not play a major role in the acquisition of the metastatic phenotype in human melanoma. Mutations in p53 are infrequent and do not correlate with the metastatic potential of human melanoma cells while p16/CDKN2 abnormalities are frequent, but are not pre-requisite for the acquisition of the metastatic phenotype. On the other hand, the tyrosine-kinase receptor c-KIT and the cell adhesion molecule MCAM/MUC-18 play active roles in the progression of human melanoma. Metastatic melanoma cells overexpress MCAM and do not express the c-KIT receptor. Enforced c-KIT expression in metastatic cells significantly inhibited their growth and metastatic potential in nude mice. Furthermore, 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. Ectopic expression of MCAM into primary cutaneous melanoma cells enhanced their tumorigenicity and metastatic ability in vivo. We found that both genes, c-KIT and MCAM, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. We therefore propose that loss of AP-2 might be a crucial event in the progression of human melanoma.
Luca
M R
MR
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Bar-Eli
M
M
D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D014408:Biomarkers, Tumor; D051929:CD146 Antigen; D015197:Carcinogenicity Tests; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D019006:Neural Cell Adhesion Molecules; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D051929:CD146 Antigen; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497902:MCAM protein, human; C497903:Mcam protein, mouse; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D016159:Tumor Suppressor Protein p53; D019009:Proto-Oncogene Proteins c-kit