LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients
LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients
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DOI：
10.1002/path.5186
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发表时间：
2019-01
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通讯作者：
Yuan Xie;Anders Sundström;N. Maturi;E-Jean Tan;Voichita D. Marinescu;M. Jarvius;Malin Tirfing;Chuan Jin;Lei Chen;M. Essand;F. Swartling;Sven Nelander;Yiwen Jiang;Lene Uhrbom
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作者：
Yuan Xie;Anders Sundström;N. Maturi;E-Jean Tan;Voichita D. Marinescu;M. Jarvius;Malin Tirfing;Chuan Jin;Lei Chen;M. Essand;F. Swartling;Sven Nelander;Yiwen Jiang;Lene Uhrbom
胶质母细胞瘤（GBM）是最常见和致命的原发性恶性脑肿瘤，缺乏有效的治疗和预测性生物标志物。上皮干细胞标记物亮氨酸富重复G蛋白偶联受体5 （LGR5）在GBM中的表达已被描述，但其功能作用尚未得到明确阐明。在这里，我们研究了LGR5在大量患者来源的GBM干细胞（GSC）培养库中的作用。使用体外和体内方法分析了LGR5过表达或缺失的后果，结果表明，在LGR5表达最高（LGR5high）的人群中，存在两种表型不同的群体：一种依赖于LGR5的恶性特性，另一种不受LGR5表达变化的影响。通过极限稀释试验（ELDA）测量，LGR5反应培养物具有显著更高的自我更新能力，并且与LGR5高ELDAhigh培养物相比，这些LGR5高ELDAhigh培养物也明显更具恶性和侵袭性。这表明单独的LGR5表达不能作为LGR5反应性的严格标志。在寻找其他生物标志物的过程中，我们发现LPAR4、CCND2和OLIG2在LGR5应答的GSC培养物中显著上调，我们发现OLIG2和LGR5可以预测GSC辐射和药物应答。总的来说，我们发现LGR5在患者来源的GSC培养物的一个子集中调节恶性表型，这支持了它作为预测GBM生物标志物的潜力。版权所有©2018英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient‐derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5high), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5‐responding cultures could be identified by their significantly higher self‐renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5high‐ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high‐ELDAlow cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5‐responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient‐derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.