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Cutaneous and uveal melanoma provide excellent model systems for studying the processes of tumor progression, tumor cell invasion, metastasis and immunosurveillance. Studies that incorporate both of these models can provide novel insights into how tumor cells of common embryonic origin may respond to different environments and conditions, since cutaneous melanoma cells appear to metastasize by non-hematogenous (lymphatic) routes while uveal melanoma cells metastasize primarily through the blood. Microarray gene chip analyses have shown that aggressive cutaneous and uveal melanoma cells coexpress multiple phenotype-specific genes, which include genes previously thought specific to other cell types. These observations suggested that aggressive melanoma cells may undergo a genetic reversion to a pluripotent, embryonic-like (plastic) phenotype. Vasculogenic mimicry represents a remarkable example of tumor cell plasticity and is characterized by the unusual ability of aggressive human melanoma tumor cells to form tubular structures and patterned networks in three-dimensional culture reminiscent of embryonic vasculogenesis. Furthermore, extracellular matrices preconditioned by aggressive melanoma cells induce the aggressive, vasculogenic mimicry phenotype in poorly aggressive cells. Microarray analyses also supported previous observations that human leukocyte antigen (HLA) class I molecules are up-regulated and HLA class II molecules are down-regulated in aggressive uveal melanoma cells, which could facilitate an escape from immunosurveillance by natural killer cell activity during hematogenous metastasis. However, the up-regulation of HLA class I and down-regulation of HLA class II on the C8161 aggressive cutaneous melanoma cells compared to the poorly aggressive cutaneous melanoma cells reported in this review is contrary to previously published results for cutaneous melanoma and suggest that the aggressive cutaneous melanoma cell line could have been derived from a metastatic foci developed from a hematogenous (not lymphatic) metastasis. These observations offer unique perspectives regarding the plastic nature of aggressive melanoma cells that will continue to challenge our current thinking of identifying and targeting tumor cells that may masquerade as other cell types, yet may provide new prognostic markers for tumor detection, clinical diagnosis and novel therapeutic intervention strategies. [Copyright &y& Elsevier]

Cutaneous melanoma has been increasing at an alarming rate over the past two decades, however, there are no acceptable histopathological markers that classify various stages of melanoma progression. Recently, the molecular analysis of cancer has contributed significantly to our understanding of the cellular and molecular underpinnings of tumor progression. The data summarized in this review describe the molecular signature of aggressive cutaneous melanoma cells as that of multiple phenotypes which may be similar to a pluripotent, embryonic-like phenotype. An example of the plasticity of this phenotype is demonstrated by the ability of aggressive melanoma cells to engage in vasculogenic mimicry and neovascularization. A review of the current data demonstrating important cellular and molecular determinants of human melanoma vasculogenic mimicry is presented. These findings should stimulate additional studies to address the biological relevance of the multiple molecular phenotypes expressed by aggressive melanoma cells which may lead to the development of new diagnostic markers and therapeutic targets for clinical intervention. [Copyright &y& Elsevier]