Heterogeneity and Plasticity of Melanoma: Challenges of Current Therapies

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The heterogeneity and plasticity of aggressive melanoma presents formidable challenges in the design of current therapies. Plasticity is defined as the phenotype of cancer cells expressing properties normally related to stem cells, including the expression of genes associated with multiple cellular phenotypes and appearing as undifferentiated, embryonic-like cells. The multipotent phenotype of these tumor cells, expressing vascular, embryonic, and cancer stem cell (CSC) capabilities, offers new insights into their functional adaptation and resistance to current therapies. This chapter highlights major advances in research that (i) help clarify the underlying challenges associated with angiogenesis inhibitor therapy; (ii) discuss important implications of the discovery of reactivation of the normally dormant Nodal embryonic signaling pathway that underlies the CSC phenotype, unregulated tumor growth and metastasis, and resistance to current therapies; and (iii) demonstrate the advantage of using combinatorial strategies to effectively target heterogeneous melanoma subpopulations to eliminate relapse and disease progression.