The very first step from a normal cell to a benign lesion appears to be an event not dictated by genetic alterations. Instead melanocytes escape from keratinocytes through loss of E-cadherin expression. The nature of these changes remains to be elucidated. At the transition from RGP to VGP, one or more genetic hits must occur.
Cells then begin to proliferate more rapidly and develop stroma and undergo angiogenesis.
Changes in adhesion receptor expression and function further accelerate progression. The final step, metastasis, is dictated by endogenous oncogenes and tumor suppressor genes, and by exogenous interactions with the host. Metastatic cells have a highly unstable phenotype and can rapidly adapt to selective pressure, allowing the cells to survive even under the most unfavorable circumstances. Future studies to further dissect each step of melanoma progression should lead to the development of more specific and effective therapies.