Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.
Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.
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DOI：
10.1158/0008-5472.can-09-0167
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Kerbel RS
中科院分区：
文献类型：
--
作者：
Folkins C;Shaked Y;Man S;Tang T;Lee CR;Zhu Z;Hoffman RM;Kerbel RS
癌症干细胞（CSC）由于其自我更新能力和无限增殖潜力而被预测为肿瘤进展的关键驱动因素。一个新兴的研究领域表明，CSC还可以通过促进肿瘤血管生成来支持肿瘤进展。为了研究CSC如何促进肿瘤血管发育，我们使用了一种比较C6胶质瘤细胞系的肿瘤异种移植物的方法，所述C6胶质瘤细胞系含有低或高分数的CSC。与CSC-低肿瘤相比，CSC-高肿瘤表现出增加的微血管密度和血液灌注，并诱导骨髓来源的内皮祖细胞（EPC）的动员和肿瘤募集增加。与CSC低培养物相比，CSC高C6细胞培养物在体外也诱导更高水平的内皮细胞增殖和小管组织化。CSC-高培养物和肿瘤表达增加水平的促血管生成因子血管内皮生长因子和基质衍生因子1，并且当通过任一因子的信号传导被阻断时，在CSC-高培养物和肿瘤中观察到血管生成的所有方面，包括微血管密度、灌注、EPC动员/募集和内皮细胞活性的刺激，降低至与CSC-低培养物/肿瘤中观察到的水平相当的水平。这些结果表明，CSC有助于肿瘤血管生成，促进局部内皮细胞活性和全身血管生成过程涉及骨髓来源的EPC在血管内皮生长因子依赖性和基质衍生因子1依赖性的方式。
Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow–derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow–derived EPC in a vascular endothelial growth factor–dependent and stromal-derived factor 1–dependent manner.