Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
Nature. 2010 Dec 9;468(7325):824-8. doi: 10.1038/nature09557. Epub 2010 Nov 21.
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 indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. 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.
胶质母细胞瘤是一种高度血管生成的恶性肿瘤，新形成的血管被认为是通过脑毛细血管的发芽而产生的。最近的研究表明，胶质母细胞瘤中存在一群胶质母细胞瘤干细胞（GSCs），这表明这些细胞的后代可能不仅局限于神经谱系。正常的神经干细胞能够分化为功能性内皮细胞。神经干细胞和内皮细胞之间的联系在胶质母细胞瘤中似乎至关重要，其中癌症干细胞与血管龛密切相互作用，并通过释放血管内皮生长因子（VEGF）和基质衍生因子 1（refs 5-9）来促进血管生成。在这里，我们表明胶质母细胞瘤中的内皮细胞数量（范围为 20-90%，平均值为 60.7%）存在与肿瘤细胞相同的基因组改变，这表明血管内皮的很大一部分具有肿瘤起源。血管内皮包含了一部分肿瘤起始细胞，这些细胞在免疫缺陷小鼠中产生了高度血管化的间变性肿瘤，并具有血管生成拟态区域。在体外培养条件下，GSCs 可以生成具有内皮细胞表型和功能特征的后代。同样，将 GSCs 原位或皮下注射到免疫缺陷小鼠中，也会产生肿瘤异种移植物，其血管主要由人内皮细胞组成。在小鼠异种移植物中对 GSCs 产生的内皮细胞进行选择性靶向，导致肿瘤减少和退化，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新的肿瘤血管生成机制，可能解释了几种恶性肿瘤中存在癌症衍生的内皮样细胞的原因。
