HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis.
HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis.
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DOI：
10.3389/fonc.2016.00057
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发表时间：
2016
影响因子：
4.7
通讯作者：
Mao JH
中科院分区：
文献类型：
--
作者：
Barcellos-Hoff MH;Mao JH
对辐射引起的增加癌症风险的生物过程的明确的机械理解可用于预测医疗用途的健康后果，如放射治疗或职业照射，如宇航员在深空旅行期间的职业照射。在这里，我们回顾了目前的概念，癌变作为一个多细胞的过程中，转化细胞逃脱正常组织的控制，包括免疫系统，并建立一个肿瘤微环境。我们讨论了两大类可能增加癌症的辐射效应的贡献：由于直接能量沉积而发生的辐射靶向效应，例如，DNA损伤和由细胞信号传导变化引起的非靶向效应（NTE），例如，基因组不稳定性尚不清楚高Z和能量（HZE）粒子辐射的潜在更大致癌效应是否是NTE的相对贡献或程度的函数，还是由于独特的NTE。我们使用放射/遗传乳腺嵌合体小鼠乳腺癌模型解决了这个问题。我们的实验表明，NTE促进更具侵袭性的癌症，如增加的生长速率、转录组特征和转移所证明的，并且HZE颗粒NTE比参考γ辐射更有效。新出现的证据表明，HZE照射抑制抗肿瘤免疫。这些研究引起了人们的关注，即HZE辐射暴露不仅增加了患癌症的可能性，而且还可能促进进展为更具侵袭性的癌症，死亡风险更大。
Clear mechanistic understanding of the biological processes elicited by radiation that increase cancer risk can be used to inform prediction of health consequences of medical uses, such as radiotherapy, or occupational exposures, such as those of astronauts during deep space travel. Here, we review the current concepts of carcinogenesis as a multicellular process during which transformed cells escape normal tissue controls, including the immune system, and establish a tumor microenvironment. We discuss the contribution of two broad classes of radiation effects that may increase cancer: radiation targeted effects that occur as a result of direct energy deposition, e.g., DNA damage, and non-targeted effects (NTE) that result from changes in cell signaling, e.g., genomic instability. It is unknown whether the potentially greater carcinogenic effect of high Z and energy (HZE) particle radiation is a function of the relative contribution or extent of NTE or due to unique NTE. We addressed this problem using a radiation/genetic mammary chimera mouse model of breast cancer. Our experiments suggest that NTE promote more aggressive cancers, as evidenced by increased growth rate, transcriptomic signatures, and metastasis, and that HZE particle NTE are more effective than reference γ-radiation. Emerging evidence suggest that HZE irradiation dampens antitumor immunity. These studies raise concern that HZE radiation exposure not only increases the likelihood of developing cancer but also could promote progression to more aggressive cancer with a greater risk of mortality.