Molecular biology of cutaneous melanoma

Melanoma, like all malignant tumors, is a genetic disease. Its progression is driven by a series of accumulating genetic changes. Genetic alterations involved in melanoma can activate inductive processes (oncogenes) or block negative pathways (suppressor genes). Most tumor suppressor genes can be divided into two groups, called gatekeepers and caretakers. Inactivation of gatekeepers may occur in about half of all melanoma cases. The development of human cutaneous melanoma is a consequence of a multistep process. This process involves formation of nevi from normal melanocytes, a radial growth phase, and a subsequent vertical growth phase. Finally, metastatic disease may be developed. The molecular mechanisms leading to human melanoma are not well known. However, some important genetic changes involved in melanoma development were recognized. An impressive list of experiments supports a role of p16/INK4a in melanoma formation. This protein is strongly involved in cell cycle-control machinery. Inactivation of p16/INK4a leads to uncontrolled cell proliferation. The gatekeepers other than p16/INK4a also play a part in melanoma formation. These are for example p19/INK4d, PTEN, as well as p53. The data obtained from gene expression profiling indicate that inactivation of gatekeepers plays an essential role in melanoma development. However, some oncogenes are also strongly involved in this process. One of these is CDK4, a target of p16’s biochemical inhibitory activity. Metastatic melanoma cells do not express the c-KIT (CD117) receptor. Expression of c-KIT is regulated by the transcription factor AP-2. Expression of AP-2 is not detected in metastatic melanoma cells. The loss of AP-2 expression seems to be a crucial event in the development of metastatic human melanoma.