Patient-derived glioblastoma stem cells respond differentially to targeted therapies
Patient-derived glioblastoma stem cells respond differentially to targeted therapies
复制标题
DOI：
10.18632/oncotarget.13415
复制
发表时间：
2016-12-27
期刊：
影响因子：
--
通讯作者：
Sheng, Zhi
中科院分区：
文献类型：
--
作者：
Kanabur, Pratik;Guo, Sujuan;Sheng, Zhi
胶质母细胞瘤的预后不佳至少部分归因于难以根除胶质母细胞瘤干细胞（GSC）。然而，这种困难是否是由GSC对药物的差异反应引起的仍有待确定。为了解决这个问题，我们从已建立的细胞系、异种移植物或患者标本中分离并表征了10个GSC系。六个线形成球在常规培养条件下，而其余四个线生长为单层。这些粘附线仅在涂有聚甲基丙烯酸2-羟乙酯的平板中形成球体。GSC的自我更新能力各不相同，球体形成所需的细胞密度范围为4至23.8个细胞/孔。此外，单个非贴壁GSC在4 - 7天内保持静止或分裂成两个细胞。巢蛋白或胶质细胞酸性蛋白的表达进一步证实了GSCs的干细胞身份。在免疫缺陷小鼠中注射的两种GSC细胞系中，只有一种细胞系在两个月内形成肿瘤。NOTCH 1和血小板衍生生长因子受体α的蛋白水平与GSC对...分泌酶抑制剂IX或伊马替尼，分别抑制这两种蛋白质的两种化合物。此外，替莫唑胺和连接蛋白43抑制剂的组合强烈抑制GSC的生长。总的来说，我们的结果表明，患者来源的GSC在培养中表现出不同的生长速率，具有形成肿瘤的不同能力，并且对靶向治疗具有不同的反应。我们的研究结果强调了患者来源的GSC在胶质母细胞瘤研究和治疗开发中的重要性。
The dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to.-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.