Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Nature. 2010 Dec 9;468(7325):829-33. doi: 10.1038/nature09624. Epub 2010 Nov 21.
Glioblastoma (GBM) is among the most aggressive of human cancers. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined. Here we demonstrate that a subpopulation of endothelial cells within glioblastomas harbour the same somatic mutations identified within tumour cells, such as amplification of EGFR and chromosome 7. We additionally demonstrate that the stem-cell-like CD133(+) fraction includes a subset of vascular endothelial-cadherin (CD144)-expressing cells that show characteristics of endothelial progenitors capable of maturation into endothelial cells. Extensive in vitro and in vivo lineage analyses, including single cell clonal studies, further show that a subpopulation of the CD133(+) stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate CD133(+)/CD144(+) progenitor cell. The findings are supported by genetic studies of specific exons selected from The Cancer Genome Atlas, quantitative FISH and comparative genomic hybridization data that demonstrate identical genomic profiles in the CD133(+) tumour cells, their endothelial progenitor derivatives and mature endothelium. Exposure to the clinical anti-angiogenesis agent bevacizumab or to a γ-secretase inhibitor as well as knockdown shRNA studies demonstrate that blocking VEGF or silencing VEGFR2 inhibits the maturation of tumour endothelial progenitors into endothelium but not the differentiation of CD133(+) cells into endothelial progenitors, whereas γ-secretase inhibition or NOTCH1 silencing blocks the transition into endothelial progenitors. These data may provide new perspectives on the mechanisms of failure of anti-angiogenesis inhibitors currently in use. The lineage plasticity and capacity to generate tumour vasculature of the putative cancer stem cells within glioblastoma are novel findings that provide new insight into the biology of gliomas and the definition of cancer stemness, as well as the mechanisms of tumour neo-angiogenesis.
胶质母细胞瘤（GBM）是人类癌症中最具侵袭性的一种。GBM 的一个主要特征是广泛的异常血管网络，其特征为肾小球样结构和内皮细胞增生。然而，血管生成的机制和肿瘤内皮细胞的起源仍然定义不清。在这里，我们证明了 GBM 中的内皮细胞亚群携带有肿瘤细胞中相同的体细胞突变，如 EGFR 和 7 号染色体的扩增。我们还证明了干细胞样 CD133(+) 亚群包括一部分表达血管内皮钙黏蛋白（VE-cadherin，CD144）的细胞，这些细胞具有内皮祖细胞的特征，能够成熟为内皮细胞。广泛的体外和体内谱系分析，包括单细胞克隆研究，进一步表明 CD133(+) 干细胞样细胞亚群的一部分具有多能性，能够沿着肿瘤和内皮谱系分化，可能通过中间的 CD133(+)/CD144(+) 祖细胞。这些发现得到了来自癌症基因组图谱（TCGA）的特定外显子的遗传研究、定量荧光原位杂交（FISH）和比较基因组杂交（CGH）数据的支持，这些数据表明 CD133(+) 肿瘤细胞、其内皮祖细胞衍生物和成熟内皮细胞具有相同的基因组谱。暴露于临床抗血管生成药物贝伐单抗或γ-分泌酶抑制剂，以及 shRNA 敲低研究表明，阻断 VEGF 或沉默 VEGFR2 可抑制肿瘤内皮祖细胞向内皮细胞的成熟，但不抑制 CD133(+) 细胞向内皮祖细胞的分化，而 γ-分泌酶抑制或 NOTCH1 沉默则阻断向内皮祖细胞的转化。这些数据可能为目前使用的抗血管生成抑制剂失效的机制提供新的视角。胶质母细胞瘤中假定的癌症干细胞的谱系可塑性和生成肿瘤血管的能力是新的发现，为胶质瘤的生物学和癌症干性的定义以及肿瘤新生血管生成的机制提供了新的见解。
