Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum
Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum
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DOI：
10.1073/pnas.0804186105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Saran, Anna
中科院分区：
文献类型：
--
作者：
Mancuso, Mariateresa;Pasquali, Elmanuela;Saran, Anna
辐射生物学的中心法则，即电离辐射的生物效应是受辐射细胞中发生的 DNA 损伤的直接后果，受到以下观察的挑战：由于细胞间通讯或受辐射细胞释放的可溶性因子，未暴露的“旁观者细胞”邻近直接击中的细胞发生遗传/表观遗传变化。迄今为止，绝大多数这些效应都是在细胞培养系统中描述的，而生物体内生物学后果的体内验证和评估仍然不确定。在这里，我们将新生小鼠小脑描述为精确的体内模型，用于检测、量化和机械剖析辐射旁观者反应。在体内旁观者小脑中诱导 DNA 双链断裂和细胞凋亡。伴随这些遗传事件，我们报告了对放射敏感的 Patched-1 (Ptch1) 杂合小鼠的小脑在对身体其余部分进行 X 射线照射后，旁观者相关的肿瘤诱导。我们进一步表明，遗传损伤是体内致癌旁观者反应的关键组成部分，并提供证据支持间隙连接细胞间通讯（GJIC）在中枢神经系统（CNS）旁观者信号传递中的作用。这些结果代表了第一个原理证明，即旁观者效应是具有致癌潜力的真实体内事件，并暗示需要重新评估目前用于估计辐射相关健康风险的方法。
The central dogma of radiation biology, that biological effects of ionizing radiation are a direct consequence of DNA damage occurring in irradiated cells, has been challenged by observations that genetic/epigenetic changes occur in unexposed "bystander cells" neighboring directly-hit cells, due to cell-to-cell communication or soluble factors released by irradiated cells. To date, the vast majority of these effects are described in cell-culture systems, while in vivo validation and assessment of biological consequences within an organism remain uncertain. Here, we describe the neonatal mouse cerebellum as an accurate in vivo model to detect, quantify, and mechanistically dissect radiation-bystander responses. DNA double-strand breaks and apoptotic cell death were induced in bystander cerebellum in vivo. Accompanying these genetic events, we report bystander-related tumor induction in cerebellum of radiosensitive Patched-1 (Ptch1) heterozygous mice after x-ray exposure of the remainder of the body. We further show that genetic damage is a critical component of in vivo oncogenic bystander responses, and provide evidence supporting the role of gap-junctional intercellular communication (GJIC) in transmission of bystander signals in the central nervous system (CNS). These results represent the first proof-of-principle that bystander effects are factual in vivo events with carcinogenic potential, and implicate the need for re-evaluation of approaches currently used to estimate radiation-associated health risks.