Tumor and Stem Cell Biology CD133þ Melanoma Subpopulations Contribute to Perivascular Niche Morphogenesis and Tumorigenicity through Vasculogenic Mimicry

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 CD133þ and ABCB5þ subpopulations are colocalized in melanomas in perivascular niches that contain CD144 (VE-cadherin)þ 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 comparedwith controls. CD133KD cells also lacked the ability to formCD144þVM-like channels in amanner that was associatedwith a depletion of theABCB5þ cell subpopulation. Finally, CD133KDcells exhibited poorer tumor growth in vivo. Taken together, ourfindings corroboratemodels inwhichCD133þ/ABCB5þmelanoma cells reside in a complex anastomosing microvascular niche that encompasses CD144þ VM channels as well as authentic endothelial cell-lined blood vessels. Further, they indicate that CD133þ cells act as stem-like cells, which drive tumor growth by promoting VM and the morphogenesis of a specialized perivascular niche in melanoma. Cancer Res; 72(19); 5111–8. 2012 AACR.