Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
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DOI：
10.1016/j.stem.2017.04.009
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发表时间：
2017-07-06
期刊：
影响因子：
23.9
通讯作者：
De Maria, Ruggero
中科院分区：
文献类型：
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作者：
Haas, Tobias L.;Sciuto, Maria Rita;De Maria, Ruggero
胶质母细胞瘤干细胞样细胞（GSC）的功能相关标志物具有治疗靶向治疗这种侵袭性疾病的潜力。在这里，我们使用了数以千计的单克隆抗体的产生和筛选，以寻找受体和信号通路，优先富集在GSC。我们鉴定了整合素α 7（ITGA 7）作为GSC和原发性高级别胶质瘤标本中的主要层粘连蛋白受体。综合数据集的mRNA谱分析显示，ITGA7高表达与低级别和高级别胶质瘤患者的生存率呈负相关。体外和体内分析表明，ITGA 7在GSC的生长和侵袭性中起着关键的功能作用。我们还发现，通过RNAi靶向ITGA 7或阻断mAb损害了层粘连蛋白诱导的信号传导，并且它导致肿瘤植入的显著延迟以及肿瘤大小和侵袭的显著减少。因此，我们的数据突出了ITGA 7作为胶质母细胞瘤生物标志物和候选治疗靶点。
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin alpha 7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low-and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.