Targeting Ephrin Receptor Tyrosine Kinase A2 with a Selective Aptamer for Glioblastoma Stem Cells
Targeting Ephrin Receptor Tyrosine Kinase A2 with a Selective Aptamer for Glioblastoma Stem Cells
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DOI：
10.1016/j.omtn.2020.02.005
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发表时间：
2020-06-05
影响因子：
8.8
通讯作者：
Condorelli, Gerolama
中科院分区：
文献类型：
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作者：
Affinito, Alessandra;Quintavalle, Cristina;Condorelli, Gerolama
尽管放疗和化疗对胶质母细胞瘤 (GBM) 治疗有好处，但大多数患者在初始治疗后会出现复发。复发性或进展性 GBM 通常对标准治疗不再有反应，这与患者预后不佳有关。 GBM干细胞（GSC）是对放疗和化疗具有抵抗力的细胞亚群，在肿瘤复发中发挥着重要作用。 GSC 的靶向和新标记物的鉴定是制定根除 GBM 创新策略的关键问题。通过差异细胞SELEX（指数富集配体的系统进化），我们最近描述了两种RNA适体，即40L序列及其截短形式A40s，能够结合人GSC的细胞表面。两种适体都对干细胞样生长的 GBM 细胞具有选择性，并快速内化到靶细胞中。在这项研究中，我们证明它们与细胞的结合是通过直接识别肝配蛋白 A 型受体 2 (EphA2) 介导的。从功能上讲，这两种适体能够抑制 GSC 的细胞生长、干性和迁移。此外，A40s 能够穿过血脑屏障 (BBB)，并且在体外实验中在血清中稳定。这些结果表明 40L 和 A40s 代表了 GBM 的创新潜在治疗工具。
Despite the benefits associated with radiotherapy and chemotherapy for glioblastoma (GBM) treatment, most patients experience a relapse following initial therapy. Recurrent or progressive GBM usually does not respond anymore to standard therapy, and this is associated with poor patient outcome. GBM stem cells (GSCs) are a subset of cells resistant to radiotherapy and chemotherapy and play a role in tumor recurrence. The targeting of GSCs and the identification of novel markers are crucial issues in the development of innovative strategies for GBM eradication. By differential cell SELEX (systematic evolution of ligands by exponential enrichment), we have recently described two RNA aptamers, that is, the 40L sequence and its truncated form A40s, able to bind the cell surface of human GSCs. Both aptamers were selective for stem-like growing GBM cells and are rapidly internalized into target cells. In this study, we demonstrate that their binding to cells is mediated by direct recognition of the ephrin type-A receptor 2 (EphA2). Functionally, the two aptamers were able to inhibit cell growth, stemness, and migration of GSCs. Furthermore, A40s was able to cross the blood-brain barrier (BBB) and was stable in serum in in vitro experiments. These results suggest that 40L and A40s represent innovative potential therapeutic tools for GBM.