The molecular changes associated with the transition of
melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not yet well defined. We have demonstrated that the progression of human
melanoma is associated with loss of expression of the
transcription factor AP-2. In metastatic
melanoma cells, this loss resulted in overexpression of MCAM/MUC18, MMP-2, the
thrombin receptor (PAR-1), and lack of c-KIT expression. The transition from RGP to VGP is also associated with overexpression of the
angiogenic factor IL-8. Additionally, the transition of
melanoma cells from RGP to VGP is associated with overexpression of the
transcription factors CREB and ATF-1, both of which may act as survival factors for human
melanoma cells. Inactivation of CREB/ATF-1 activities in metastatic
melanoma cells by dominant-negative CREB or by anti-ATF-1 single chain
antibody fragment (ScFv), resulted in deregulation of MMP-2 and MCAM/MUC18, increased the sensitivity of
melanoma cells to apoptosis, and inhibition of their tumorigenicity and metastatic potential in vivo. In this prospect article, we summarize our data on the role of AP-2 and CREB/ATF-1 in the progression of human
melanoma and report on the development of new fully human
antibodies anti-MCAM/MUC18 and anti-IL-8 which could serve as new modalities for the treatment of
melanoma.