Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells
Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells
复制标题
DOI：
10.1038/nature09557
复制
发表时间：
2010-12-09
期刊：
影响因子：
64.8
通讯作者：
De Maria, Ruggero
中科院分区：
文献类型：
--
作者：
Ricci-Vitiani, Lucia;Pallini, Roberto;De Maria, Ruggero
胶质母细胞瘤是一种高度血管生成性的恶性肿瘤，其新生血管被认为是由预先存在的脑毛细血管出芽形成的。最近有研究表明，一群胶质母细胞瘤干细胞样细胞（GSCs）维持着胶质母细胞瘤的生长（1,2），这意味着这些细胞的后代可能并不局限于神经谱系（3）。正常的神经干细胞能够分化为功能性内皮细胞（4）。在胶质母细胞瘤中，神经干细胞和内皮细胞区室之间的联系似乎至关重要，其中癌干细胞与血管微环境密切相互作用，并通过释放血管内皮生长因子（VEGF）和基质衍生因子1（参考文献5 - 9）促进血管生成。在此我们发现，胶质母细胞瘤中数量不等（范围为20 - 90%，平均60.7%）的内皮细胞携带与肿瘤细胞相同的基因组改变，这表明很大一部分血管内皮具有肿瘤起源。血管内皮包含一组致瘤细胞，这些细胞在免疫功能低下的小鼠中产生高度血管化的间变性肿瘤，并伴有血管生成拟态区域。在血管内皮条件下对GSCs进行体外培养，产生了具有内皮细胞表型和功能特征的后代。同样，在免疫功能低下的小鼠中对GSCs进行原位或皮下注射，产生了肿瘤异种移植物，其血管主要由人内皮细胞组成。对小鼠异种移植物中GSCs产生的内皮细胞进行选择性靶向，导致肿瘤缩小和退化，这表明GSC衍生的内皮血管具有功能相关性。这些发现描述了一种肿瘤血管生成的新机制，并可能解释了在几种恶性肿瘤中存在肿瘤衍生的内皮样细胞的原因。
Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas(1,2) indicates that the progeny of these cells may not be confined to the neural lineage(3). Normal neural stem cells are able to differentiate into functional endothelial cells(4). The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.