The Brain Microenvironment Preferentially Enhances the Radioresistance of CD133+ Glioblastoma Stem-like Cells
The Brain Microenvironment Preferentially Enhances the Radioresistance of CD133+ Glioblastoma Stem-like Cells
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DOI：
10.1593/neo.111794
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Tofilon, Philip J.
中科院分区：
文献类型：
--
作者：
Jamal, Muhammad;Rath, Barbara H.;Tofilon, Philip J.
从胶质母细胞瘤（GBM）CD 133（+）肿瘤干细胞样细胞（TSC）开始的脑肿瘤异种移植物由TSC和非TSC亚群组成，模拟原位GBM的表型异质性。鉴于体外GBM细胞的放射敏感性与患者的治疗反应之间的差异表明微环境在GBM放射抗性中的作用，我们比较了在体外和原位条件下照射的TSC和非TSC的反应。作为在单个细胞水平测定的放射应答的量度，在CD 133（+）细胞及其分化的（CD 133（-））后代中定量γ H2 AX和53 BP 1病灶。在体外条件下，CD 133（+）和CD 133（-）细胞在照射后的病灶诱导或消散方面没有差异。然而，与相同肿瘤内的CD 133（-）对应物相比，从TSC开始的原位异种移植物的照射导致在CD 133（+）细胞中诱导较少的γ H2 AX和53 BP 1灶。异种移植物照射导致肿瘤生长延迟约7天，照射后7天CD 133（+）细胞百分比相应增加，持续至神经系统症状发作。这些结果表明，尽管在体外生长条件下，TSC和非TSC的放射反应没有差异，但在脑内生长条件下，CD 133（+）细胞具有相对的放射抗性。尽管这些发现与TSC作为GBM辐射抗性决定因素的怀疑作用一致，但这些数据也说明了细胞辐射抗性对脑微环境的依赖性。
Brain tumor xenografts initiated from glioblastoma (GBM) CD133(+) tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, gamma.H2AX and 53BP1 foci were quantified in CD133(+) cells and their differentiated (CD133(-)) progeny. Under in vitro conditions, no difference was detected between CD133(+) and CD133(-) cells in foci induction or dispersal after irradiation. However, irradiation of orthotopic xenografts initiated from TSCs resulted in the induction of fewer gamma H2AX and 53BP1 foci in CD133(+) cells compared to their CD133(-) counterparts within the same tumor. Xenograft irradiation resulted in a tumor growth delay of approximately 7 days with a corresponding increase in the percentage of CD133(+) cells at 7 days after radiation, which persisted to the onset of neurologic symptoms. These results suggest that, although the radioresponse of TSCs and non-TSCs does not differ under in vitro growth conditions, CD133(+) cells are relatively radioresistant under intracerebral growth conditions. Whereas these findings are consistent with the suspected role for TSCs as a determinant of GBM radioresistance, these data also illustrate the dependence of the cellular radioresistance on the brain microenvironment.