Abstract
Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1–6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.
Highlights
Radiotherapy is one of the most important treatments for various malignancies, including lung cancer, liver cancer, nasopharyngeal carcinoma, and other tumors [1,2,3].radiation can cause direct damage to the targeted tissue and induce some unexpected effects on distal nonirradiated tissues [4], referred to as the abscopal effect
This study demonstrated for the first time that the high-dose of partial thoracic irradiation could induce abscopal damage in bone marrow of mice, and the signaling factors of this Radiation-induced abscopal effect (RIAE) were further investigated
To study the abscopal effect of lung irradiation, an animal model was established by irradiating the right lung of mouse with fractionated doses of X-rays for three consecutive days (8 Gy/per day, three days), the lung, femur and blood of the mice were collected at day one, three, and seven after this thoracic irradiation (Th-IR) for further analysis (Figure 1A)
Summary
Radiotherapy is one of the most important treatments for various malignancies, including lung cancer, liver cancer, nasopharyngeal carcinoma, and other tumors [1,2,3]. The incidence of abscopal effects is critically determined by signaling factors from irradiated cells to distant cells. In the process of immune activation induced by radiation, TNF-α, the most primitive and pro-inflammatory cytokine in inflammation, was approved to be an oncotoxic factor rather than to augment the anti-tumor immune responses [13]. Studies have shown that TNF-α contributes to bone marrow cell apoptosis in the total-body irradiated mice [17], there is no literature confirming the role of cytokines, especially TNF-α, in thoracic irradiation induced bone marrow damage. The potential abscopal effect caused by the irradiation of localized thorax on bone marrow has never been addressed in detail. This study demonstrated for the first time that the high-dose of partial thoracic irradiation could induce abscopal damage in bone marrow of mice, and the signaling factors of this RIAE were further investigated
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