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New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: ar how some melanoma cells gain this ability; whether through acquisition of additional mutations [104,106], and/or having arisen from a defined subpopulation of slow‐cycling self‐renewing melanoma stem‐like cells [239,240,318‐320]. The latter assumes that tumours are hierarchically organised, with a small subpopulation of tumourigenic cells with self‐renewing capacity that generate phenotypically diverse nontumourigenic progeny, in a similar manner to normal stem cell differentiation [126]. However, even after intensive effort to fully characterise melanoma stem‐like cells, research has yielded conflicting results, and has failed to clearly identify uniform sets of markers for these cells (for review see [29,126]). Some groups suggest that most melanoma cells (not just rare stem cells) actually have tumourigenic capacity [148,321‐323]. Another, more recent, concept suggests that most melanoma cells have the ability to switch between less and more active malignant states [124,287,322]. According to this model melanoma metastasis and phenotypic heterogeneity are driven by specific gene expression programs that are imposed by the cellular microenvironment, rather than by accumulation of genetic events. Melanoma cells are able to respond to microenvironmental changes by switching between a highly proliferative (low metastatic potential, leading to tumour growth), and highly invasive phenotype (motile and stem cell‐like, resulting in tumour dissemination). A highly proliferative cell phenotype shows Wnt and MITF‐driven gene expression profiles with susceptibility to TGFβ‐mediated inhibition of proliferation. By contrast, a highly invasive cell phenotype shows a TGFβ‐driven gene expression profile, with downregulation of Wnt signalling, MITF and downstream differentiation markers, and low pigmentation [124,125,324]. 105 Chapter V – General Discussion In support of this concept, an elegant study by Pinner and colleagues [287] has shown that low or non pigmented melanoma cells contained...
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