Notch信号增强促进胶质瘤干细胞/祖细胞诱导的恶性基质细胞的放射抗性。
Increased Notch Signaling Enhances Radioresistance of Malignant Stromal Cells Induced by Glioma Stem/ Progenitor Cells.
作者信息
Shen Yuntian, Chen Hua, Zhang Jinshi, Chen Yanming, Wang Mengyao, Ma Jiawei, Hong Lei, Liu Ning, Fan Qiuhong, Lu Xueguan, Tian Ye, Wang Aidong, Dong Jun, Lan Qing, Huang Qiang
机构信息
Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
Department of Neurosurgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
出版信息
PLoS One. 2015 Nov 23;10(11):e0142594. doi: 10.1371/journal.pone.0142594. eCollection 2015.
BACKGROUND
Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear.
METHODS
Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model. The survival fraction at 2 Gy (SF2) was used to evaluate the radiation resistance of ihBTC2, the human glioma stem/progenitor cell line SU3 and its radiation-resistant sub-strain SU3-5R and the rat C6 glioma cell line. The mRNA of Notch 1 and Hes1 from ihBTC2 cells were detected using qPCR before and after 4 Gy radiation. The expression of the Notch 1, pAkt and Bcl-2 proteins were investigated by Western blot. To confirm the role of the Notch pathway in the radiation resistance of ihBTC2, Notch signaling blocker gamma secretase inhibitors (GSIs) were used.
RESULTS
The ihBTC2 cells had malignant phenotypes, such as infinite proliferation, hyperpentaploid karyotype, tumorigenesis in nude mice and expression of protein markers of oligodendroglia cells. The SF2 of ihBTC2 cells was significantly higher than that of any other cell line (P<0.05, n = 3). The expression of Notch 1 and Hes1 mRNAs from ihBTC2 cells was significantly increased after radiation. Moreover, the Notch 1, pAkt and Bcl-2 proteins were significantly increased after radiation (P<0.05, n = 3). Inhibition of Notch signaling markedly enhanced the radiosensitivity of ihBTC2 cells.
CONCLUSIONS
In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells. IhBTC2 cells are more radiation-resistant than the glioma stem/progenitor cells, which may be mediated by activation of the Notch signaling pathway.
背景
在裸鼠中，胶质瘤干/祖细胞诱导产生的宿主恶性基质细胞在恶性转化后显示出比胶质瘤干/祖细胞本身更强的辐射抗性。然而，这一现象背后的机制仍不清楚。
方法
从双色编码原位胶质瘤裸鼠模型中分离并鉴定出由胶质瘤干/祖细胞2诱导产生的恶性基质细胞（GSC诱导的宿主脑肿瘤细胞，ihBTC2）。使用2 Gy时的存活分数（SF2）来评估ihBTC2、人胶质瘤干/祖细胞系SU3及其辐射抗性亚系SU3-5R以及大鼠C6胶质瘤细胞系的辐射抗性。在4 Gy辐射前后，使用qPCR检测ihBTC2细胞中Notch 1和Hes1的mRNA。通过蛋白质印迹法研究Notch 1、pAkt和Bcl-2蛋白的表达。为了证实Notch信号通路在ihBTC2辐射抗性中的作用，使用了Notch信号阻断剂γ-分泌酶抑制剂（GSIs）。
结果
ihBTC2细胞具有恶性表型，如无限增殖、超五倍体核型、在裸鼠中形成肿瘤以及少突胶质细胞蛋白标志物的表达。ihBTC2细胞的SF2显著高于任何其他细胞系（P<0.05，n = 3）。辐射后，ihBTC2细胞中Notch 1和Hes1 mRNA的表达显著增加。此外，辐射后Notch 1、pAkt和Bcl-2蛋白显著增加（P<0.05，n = 3）。抑制Notch信号显著增强了ihBTC2细胞的放射敏感性。
结论
在原位胶质瘤模型中，胶质瘤干/祖细胞诱导宿主基质细胞发生恶性转化。IhBTC2细胞比胶质瘤干/祖细胞具有更强的辐射抗性，这可能是由Notch信号通路的激活介导的。
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