电离辐射
中性粒细胞胞外陷阱
细胞外
非电离辐射
阈剂量
放射生物学
医学
放射化学
辐照
放射治疗
生物
化学
免疫学
细胞生物学
内科学
炎症
物理
光学
核物理学
作者
Álvaro Teijeira,Saray Garasa,María C. Ochoa,Sandra Sánchez-Gregorio,Gabriel Gomis,Carlos Luri‐Rey,Rafael Martı́nez-Monge,Beatrice Pinci,Karmele Valencia,Belén Palencia,Benigno Barbés Fernández,Elixabet Bolaños,Arantza Azpilikueta,Marina Garcia-Cardosa,Javier Burguete,Iñaki Eguren-Santamaría,Eneko Garate-Soraluze,Pedro Berraondo,José Luis Pérez-Gracia,Carlos de Andrea,María E. Rodríguez-Ruiz,Ignacio Melero
标识
DOI:10.1158/1078-0432.ccr-23-3860
摘要
Abstract Purpose: Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. Experimental design: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. Results: Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. Conclusions: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.
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