Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

中文翻译：

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apelin的药理靶向作用会损害胶质母细胞瘤的生长

胶质母细胞瘤是高度侵袭性的脑肿瘤，与预后极差有关。在这些肿瘤中，存在着高度可塑性自我更新的癌细胞亚群，它们保留了体外扩增的能力作为肿瘤球，可诱导小鼠肿瘤生长，并与放射抗性和化学抗性有关。尽管它们的身份和命运受到内皮细胞发出的外部信号的调节，但这种信号的性质仍然未知。在这里，我们使用质谱蛋白质组学方法来表征由脑内皮细胞释放的因子。我们报告了血管活性肽apelin作为内皮调节的胶质母细胞瘤患者源性干细胞的内皮介导的维护的中央调节器的鉴定。Apelin同源受体的遗传和药理靶向在体外消除了Apelin和内皮介导的胶质母细胞瘤患者来源细胞的扩增，并具有干样特性，并在体内抑制了肿瘤的生长。在功能上，显示出选择性的apelin受体竞争性拮抗剂在减少肿瘤扩展和延长颅内异种移植小鼠的存活方面是安全有效的。因此，apelin / apelin受体信号传导联系可以作为旁分泌信号，维持肿瘤细胞的扩张和发展，这表明apelin是胶质母细胞瘤的可治疗因子。