Translational Research Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi-Mumbai, 410210, India.
Comparative Oncology Program and Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi-Mumbai, 410210, India.
Cell Death Dis. 2018 Nov 15;9(12):1142. doi: 10.1038/s41419-018-1181-x.
Radiation-induced bystander effect (RIBE) is a poorly understood phenomenon wherein non-targeted cells exhibit effects of radiation. We have reported that cell-free chromatin (cfCh) particles that are released from dying cells can integrate into genomes of surrounding healthy cells to induce DNA damage and inflammation. This raised the possibility that RIBE might be induced by cfCh released from irradiated dying cells. When conditioned media from BrdU-labeled irradiated cells were passed through filters of pore size 0.22 µm and incubated with unexposed cells, BrdU-labeled cfCh particles could be seen to readily enter their nuclei to activate H2AX, active Caspase-3, NFκB, and IL-6. A direct relationship was observed with respect to activation of RIBE biomarkers and radiation dose in the range of 0.1-0 Gy. We confirmed by FISH and cytogenetic analysis that cfCh had stably integrated into chromosomes of bystander cells and had led to extensive chromosomal instability. The above RIBE effects could be abrogated when conditioned media were pre-treated with agents that inactivate cfCh, namely, anti-histone antibody complexed nanoparticles (CNPs), DNase I and a novel DNA degrading agent Resveratrol-copper (R-Cu). Lower hemi-body irradiation with γ-rays (0.1-50 Gy) led to activation of H2AX, active Caspase-3, NFκB, and IL-6 in brain cells in a dose-dependent manner. Activation of these RIBE biomarkers could be abrogated by concurrent treatment with CNPs, DNase I and R-Cu indicating that activation of RIBE was not due to radiation scatter to the brain. RIBE activation was seen even when mini-beam radiation was delivered to the umbilical region of mice wherein radiation scatter to brain was negligible and could be abrogated by cfCh inactivating agents. These results indicate that cfCh released from radiation-induced dying cells are activators of RIBE and that it can be prevented by treatment with appropriate cfCh inactivating agents.
辐射诱导的旁观者效应（RIBE）是一种尚未被充分了解的现象，即非靶细胞表现出辐射的效应。我们已经报道，来自死亡细胞的无细胞染色质（cfCh）颗粒可以整合到周围健康细胞的基因组中，从而诱导 DNA 损伤和炎症。这就提出了一种可能性，即 RIBE 可能是由辐照死亡细胞释放的 cfCh 诱导的。当将 BrdU 标记的辐照细胞的条件培养基通过孔径为 0.22 µm 的过滤器过滤，并与未暴露的细胞孵育时，可以看到 BrdU 标记的 cfCh 颗粒很容易进入其细胞核，从而激活 H2AX、活性 Caspase-3、NFκB 和 IL-6。在 0.1-0 Gy 的辐射剂量范围内，观察到 RIBE 生物标志物的激活与辐射剂量之间存在直接关系。我们通过 FISH 和细胞遗传学分析证实，cfCh 已稳定整合到旁观者细胞的染色体中，并导致广泛的染色体不稳定性。当用失活 cfCh 的试剂（即抗组蛋白抗体复合物纳米颗粒（CNPs）、DNase I 和新型 DNA 降解剂白藜芦醇-铜（R-Cu））预处理条件培养基时，上述 RIBE 效应可以被消除。用 γ 射线对下半身进行半体照射（0.1-50 Gy）可导致脑细胞中 H2AX、活性 Caspase-3、NFκB 和 IL-6 的剂量依赖性激活。用 CNPs、DNase I 和 R-Cu 同时处理可消除这些 RIBE 生物标志物的激活，表明 RIBE 的激活不是由于辐射散射到大脑。即使对小鼠脐带区域进行微型束辐射，也可以看到 RIBE 的激活，其中辐射对大脑的散射可以忽略不计，并且可以用 cfCh 失活剂消除。这些结果表明，来自辐射诱导的死亡细胞释放的 cfCh 是 RIBE 的激活剂，并且可以通过用适当的 cfCh 失活剂处理来预防。
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