Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy
Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy
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DOI：
10.1002/ijc.29318
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发表时间：
2015-06-01
影响因子：
6.4
通讯作者：
Pelletier, Laurent
中科院分区：
文献类型：
--
作者：
Bouchet, Audrey;Sakakini, Nathalie;Pelletier, Laurent
同步加速器微束放射治疗（MRT）依赖于同步加速器光束的空间分割成平行的微米宽光束，允许沉积六倍剂量。MRT控制了啮齿动物模型颅内肿瘤的生长，同时保留了正常脑组织。我们的目的是确定MRT对肿瘤和正常脑组织的不同影响的早期生物学过程。单向MRT （400 Gy， 50 μ m宽微束，200 μ m间距）后6小时，用芯片检测28000个转录本的表达。肿瘤组织对MRT的特异性反应包括431个问题组（316个基因）的显著转录组调节。其中30例正常脑组织未检出，MRT前后均未检出。Areg、Trib3和Nppb均下调，其余均上调。22个在MRT后2周观察到类似的表达谱，包括Ccnb1、Cdc20、Pttg1和Plk1，这些与polo样激酶（Plk）途径的有丝分裂作用有关。Areg表达的上调可能提示辐照引发肿瘤细胞出现了存活过程；而Plk1通路对有丝分裂作用的调节，与MRT后组织学观察到的肿瘤细胞动力学特征有关，可能部分解释了MRT对肿瘤生长的控制。这些肿瘤特异性反应的识别允许考虑可能增强MRT抗肿瘤作用的新策略。有什么新鲜事吗?同步微束放射治疗（MRT）的独特照射几何结构允许向脑肿瘤提供非常高剂量的辐射，对周围正常组织的损害有限。有趣的是，MRT在大脑的肿瘤和正常组织中诱导了广泛的转录组变化。在这里，在MRT后的颅内肿瘤组织中检测到316个基因的显著转录组调节。在这些基因中，有30个是脑肿瘤特异性的，在MRT前后的正常组织中未被检测到。与这些转录物变化相关的机制可能增强或限制MRT的有效性。
Synchrotron microbeam radiation therapy (MRT) relies on the spatial fractionation of a synchrotron beam into parallel micron-wide beams allowing deposition of hectogray doses. MRT controls the intracranial tumor growth in rodent models while sparing normal brain tissues. Our aim was to identify the early biological processes underlying the differential effect of MRT on tumor and normal brain tissues. The expression of 28,000 transcripts was tested by microarray 6 hr after unidirectional MRT (400 Gy, 50 mu m-wide microbeams, 200 mu m spacing). The specific response of tumor tissues to MRT consisted in the significant transcriptomic modulation of 431 probesets (316 genes). Among them, 30 were not detected in normal brain tissues, neither before nor after MRT. Areg, Trib3 and Nppb were down-regulated, whereas all others were up-regulated. Twenty-two had similar expression profiles during the 2 weeks observed after MRT, including Ccnb1, Cdc20, Pttg1 and Plk1 related to the mitotic role of the Polo-like kinase (Plk) pathway. The up-regulation of Areg expression may indicate the emergence of survival processes in tumor cells triggered by the irradiation; while the modulation of the mitotic role of Plk1 pathway, which relates to cytokinetic features of the tumor observed histologically after MRT, may partially explain the control of tumor growth by MRT. The identification of these tumor-specific responses permit to consider new strategies that might potentiate the antitumoral effect of MRT.What's new? The unique irradiation geometry of synchrotron microbeam radiation therapy (MRT) allows for the delivery of very high doses of radiation to brain tumors, with limited damage to the surrounding normal tissue. Interestingly, MRT induces a wide spectrum of transcriptomic changes in tumor and normal tissue in the brain. Here, significant transcriptomic modulation was detected for 316 genes in intracranial tumor tissue following MRT. Among those genes, 30 were specific to brain tumors, remaining undetected in normal tissue before and after MRT. Mechanisms associated with changes in those transcripts may augment or limit the effectiveness of MRT.