Transcriptional control of the melanoma malignant phenotype.

ABSTRACT

Malignant progression and tumor metastasis is a complex process enabled by the intrinsic genomic instability of the tumor cells and supported by a plethora of recruited cell types within the tumor microenvironment. Propelled by a selective pressure to overcome tissue homeostatic mechanisms, a metastatic "super-cell" emerges whose phenotype is associated with the cellular capacity for uncontrolled growth, resistance to apoptosis, high invasive potential, and effective neoangiogenesis. While genetic alterations arise early in the course of melanoma development, the progression toward metastatic disease is accompanied by deregulated expression of a number of transcription factors. In melanoma, acquisition of the metastatic phenotype involves the loss of Activator Protein-2alpha (AP-2alpha) and gain in expression of cAMP-responsive element (CRE)-binding protein/Activating Transcription Factor-1 (CREB/ATF-1) family transcription factors. Together with the upregulation of ATF-2, SNAIL/SLUG, Nuclear Factor kappaB, STAT3 and 5, and other transcription factors, these changes result in the aberrant expression of cellular adhesion molecules, matrix-degrading enzymes as well as other factors that enable a complex interaction of metastatic cells with the extracellular milieu. Similar to the case of oncogene addiction, the tumorigenicity and metastatic potential of melanoma can be greatly inhibited by altering the activity of the above-named transcription factors, therefore indicating new treatment prospects.