CD133+ melanoma subpopulations contribute to perivascular niche morphogenesis and tumorigenicity through vasculogenic mimicry.
CD133+ melanoma subpopulations contribute to perivascular niche morphogenesis and tumorigenicity through vasculogenic mimicry.
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DOI：
10.1158/0008-5472.can-12-0624
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发表时间：
2012-10-01
期刊：
影响因子：
11.2
通讯作者：
Hsu MY
中科院分区：
文献类型：
--
作者：
Lai CY;Schwartz BE;Hsu MY
表达癌症干细胞标志物如CD 133（CD 133）或ABCB 5的肿瘤细胞亚群被认为是肿瘤发生和异质性的关键，但其在黑色素瘤中的生物学意义一直存在争议。在这里，我们报告说，CD 133+和ABCB 5+亚群共定位于黑色素瘤的血管周围壁龛，含有CD 144（VE-钙粘蛋白）+黑色素瘤细胞形成血管样通道，这种现象称为血管生成拟态（VM）。RNAi介导的CD 133衰减确立了其在这些血管周围小生境的形态发生以及黑色素瘤致瘤性中的关键功能。与对照组相比，来自CD 133敲低（KD）黑色素瘤细胞的肿瘤中的小生境相关基因CD 144和ABCB 5下调。CD 133 KD细胞也缺乏形成CD 144 + VM样通道的能力，这种能力与ABCB 5+细胞亚群的耗竭有关。最后，CD 133 KD细胞在体内表现出较差的肿瘤生长。综上所述，我们的研究结果证实了CD 133 +/ABCB 5+黑色素瘤细胞存在于复杂的闭塞微血管生态位中的模型，该微血管生态位包括CD 144 + VM通道以及真实的内皮细胞内衬血管。此外，他们指出，CD 133+细胞作为干细胞样细胞，通过促进VM和黑色素瘤中专门的血管周围小生境的形态发生来驱动肿瘤生长。
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.