SOX2 is a gene located on chromosome 3q26.33 that encodes a transcription factor important to maintenance of embryonic neural crest stem cell pluripotency. We have identified rare SOX2-immunoreactive cells in normal human skin at or near the established stem cell niches. Three subsets of SOX2-positive cells were defined in these regions: those expressing only SOX2 and those that co-expressed SOX2 and either CK20 or microphthalmia-associated transcription factor , which are consistent with dichotomous differentiation of SOX2-expressing precursors along neuroendocrine (Merkel cell) or melanocytic lines , respectively. Examination of Merkel cell carcinomas confirmed nuclear SOX2 expression in this tumor type. In human patient melanoma , strong nuclear expression of SOX2 was noted in a subset of tumors , and the ability to detect SOX2 in lesional cells significantly correlated with primary tumor thickness in a survey cohort. To assess the potential role of SOX2 in melanoma growth , an in vivo tumorigenesis assay was used. Whereas SOX2 knockdown failed to influence proliferation of cultured melanoma cells in vitro , tumor xenografts generated with the SOX2-knockdown cell line showed significant decrease in mean tumor volume as compared with controls. In aggregate , these findings suggest that SOX2 is a novel biomarker for subpopulations of normal skin cells that reside in established stem cell niches and that might relate to Merkel cell and melanocyte ontogeny and tumorigenesis.
Tumor cell subpopulations that express cancer stem cell markers such as CD133 (prominin1) or ABCB5 are thought to be crucial for tumor initiation and heterogeneity, but their biological significance in melanoma has been controversial. Here, we report that CD133+ and ABCB5+ subpopulations are co-localized in melanomas in perivascular niches that contain CD144 (VE-cadherin)+ melanoma cells forming vessel-like channels, a phenomenon termed vasculogenic mimicry (VM). RNAi-mediated attenuation of CD133 established its critical function in morphogenesis of these perivascular niches as well as in melanoma tumorigenicity. Niche-associated genes CD144 and ABCB5 were downregulated in tumors derived from CD133 knockdown (KD) melanoma cells, compared to controls. CD133KD cells also lacked the ability to form CD144+ VM-like channels in a manner that was associated with a depletion of the ABCB5+ cell subpopulation. Lastly, CD133 KD cells exhibited poorer tumor growth in vivo. Taken together, our findings corroborate models in which CD133+/ABCB5+ melanoma cells reside in a complex anastomosing microvascular niche that encompasses CD144+ VM channels as well as authentic endothelial cell-lined blood vessels. Further, they indicate that CD133+ cells act as stem-like cells, which drive tumor growth by promoting VM and the morphogenesis of a specialized perivascular niche in melanoma.
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