Pharmacological targeting of apelin impairs glioblastoma growth.
Pharmacological targeting of apelin impairs glioblastoma growth.
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DOI：
10.1093/brain/awx253
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Gavard J
中科院分区：
文献类型：
--
作者：
Harford-Wright E;Andre-Gregoire G;Jacobs KA;Treps L;Le Gonidec S;Leclair HM;Gonzalez-Diest S;Roux Q;Guillonneau F;Loussouarn D;Oliver L;Vallette FM;Foufelle F;Valet P;Davenport AP;Glen RC;Bidere N;Gavard J
胶质母细胞瘤是一种侵袭性脑肿瘤，含有高度可塑性自我更新的癌细胞亚群。Harford-Wright等人表明，脑内皮细胞分泌的血管活性肽apelin调节具有干细胞样性质的胶质母细胞瘤患者来源的细胞。药理学阻断爱帕琳抑制胶质母细胞瘤细胞增殖并提高异种移植小鼠的存活率。胶质母细胞瘤是高度侵袭性的脑肿瘤，与极差的预后相关。在这些肿瘤中存在高度可塑性自我更新的癌细胞亚群，其保留了作为肿瘤球离体扩增的能力，诱导小鼠肿瘤生长，并与放射性和化学抗性有关。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，但此类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脑内皮细胞释放的因子。我们报告了血管活性肽爱帕琳作为内皮介导的维持胶质母细胞瘤患者来源的干细胞样特性的中央调节剂的鉴定。爱帕琳同源受体的遗传和药理学靶向消除了体外具有干细胞样特性的胶质母细胞瘤患者来源的细胞的爱帕琳和内皮介导的扩增，并抑制了体内肿瘤生长。在功能上，爱帕琳受体的选择性竞争性拮抗剂被证明在减少肿瘤扩张和延长颅内异种移植小鼠的存活方面是安全和有效的。因此，爱帕琳/爱帕琳受体信号传导关系可能作为维持肿瘤细胞扩增和进展的旁分泌信号起作用，表明爱帕琳是胶质母细胞瘤中的可药物化因子。
Glioblastomas are aggressive brain tumours that contain a subpopulation of highly plastic self-renewing cancer cells. Harford-Wright et al. show that the vasoactive peptide apelin, secreted by brain endothelial cells, regulates glioblastoma patient-derived cells with stem-like properties. Pharmacological blockade of apelin hampers glioblastoma cell expansion and improves survival in xenografted mice. 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.
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影响因子：
3.7
作者：
Galan-Moya EM;Treps L;Oliver L;Chneiweiss H;Vallette FM;Bidère N;Gavard J
通讯作者：
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影响因子：
24.5
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作者：
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