Expression of Genes Involved in Mouse Lung Cell Differentiation/Regulation after Acute Exposure to Photons and Protons with or without Low-Dose Preirradiation

Tian, Jing; Zhao, Weiling; Tian, Sisi; Slater, James M.; Deng, Zhiyong; Gridley, Daila S.

doi:10.1667/rr2601.1

Cited by 18 publications

(10 citation statements)

References 45 publications

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“…Low energy protons have a higher linear energy transfer and are a much denser ionizing radiation than photon and explains why at the end of their range, (known as the “Bragg peak”), these low energy protons have the potential to cause serious damage to target tissues, cells and molecules. Compared to gamma radiation, proton radiation can induce larger γ-H2AX foci (31), increased hypermethylated DNA (32), different transcriptome profiles (33) and different signaling pathways (34). More detailed investigation into the unique biological effects of proton radiation is warranted to further guide proton studies.…”

Section: Discussionmentioning

confidence: 99%

Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

Chang¹,

Wei²,

Wang³

et al. 2015

Radiation Research

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Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

Chang¹,

Wei²,

Wang³

et al. 2015

Radiation Research

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“…P irradiation led to distinct gene and protein expression profiles. 12 Mice receiving total-body irradiation with either P or X had enhanced plasma levels of transforming growth factor-β, only after X irradiation. 13 Moreover, X irradiation promoted angiogenesis, thus enhancing metastasis by upregulation of various pro-angiogenic factors.…”

Section: Introductionmentioning

confidence: 99%

“…Beside the physical advantage of P versus X irradiation and the RBE, few comparative preclinical studies have been conducted that contrast cellular/biological response to P versus X radiations. 12 , 13 , 14 , 15…”

Section: Introductionmentioning

confidence: 99%

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma

et al. 2017

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The proximity of organs at risk makes the treatment of head and neck squamous cell carcinoma (HNSCC) challenging by standard radiotherapy. The higher precision in tumor targeting of proton (P) therapy could promote it as the treatment of choice for HNSCC. Besides the physical advantage in dose deposition, few is known about the biological impact of P versus photons (X) in this setting. To investigate the comparative biological effects of P versus X radiation in HNSCC cells, we assessed the relative biological effectiveness (RBE), viability, proliferation and mRNA levels for genes involved in (lymph)angiogenesis, inflammation, proliferation and anti-tumor immunity. These parameters, particularly VEGF-C protein levels and regulations, were documented in freshly irradiated and/or long-term surviving cells receiving low/high-dose, single (SI)/multiple (MI) irradiations with P/X. The RBE was found to be 1.1 Key (lymph)angiogenesis and inflammation genes were downregulated (except for vegf-c) after P and upregulated after X irradiation in MI surviving cells, demonstrating a more favorable profile after P irradiation. Both irradiation types stimulated vegf-c promoter activity in a NF-κB-dependent transcriptional regulation manner, but at a lesser extent after P, as compared to X irradiation, which correlated with mRNA and protein levels. The cells surviving to MI by P or X generated tumors with higher volume, anarchic architecture and increased density of blood vessels. Increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in tumors generated with X-irradiated cells. Increased detection of lymphatic vessels in relapsed tumors from patients receiving X radiotherapy was consistent with these findings. This study provides new data about the biological advantage of P, as compared to X irradiation. In addition to its physical advantage in dose deposition, P irradiation may help to improve treatment approaches for HNSCC.

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“…Among such studies, most report a greater effect of protons or heavier particles on gene expression, both in terms of the number of genes responding and the magnitude of the response. This trend was reported both for the significantly responding genes in whole genome studies [22, 23], and for selected gene sets representing extracellular matrix and adhesion molecules [24], stem cell differentiation [25], or oxidative stress [26]. In contrast with these findings, one study found that genes related to inflammation showed a lower magnitude of induction in primary fibroblast cultures after proton exposure than after gamma-ray exposure [21].…”

Section: Responses In Normal Tissuementioning

confidence: 91%

Gene Expression Studies for the Development of Particle Therapy

Amundson

2018

International Journal of Particle Therapy

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Proton therapy for cancer is now in widespread use, and facilities for carbon ion therapy are showing great promise, but a more complete understanding of the mechanisms underlying particle radiation therapy is still needed in order to optimize treatment. Studies of gene expression, especially those using whole genome techniques, can provide insight into many of the questions still remaining, from the molecular mechanisms involved to predicting patient outcome. This review will summarize gene expression studies of response to proton and carbon ion beams, as well as high-energy protons and high-z high-energy particles with relevance to particle therapy. In general, most such studies find that, in comparison with x-ray or gamma-ray exposure, particle irradiation increases both the number of genes responding and the magnitude of the response. Patterns of gene expression have suggested impacts on specific pathways of relevance to radiation therapy, such as enhancement or suppression of tumor progression or metastasis. However, even within the relatively small number of studies done to date there is no clear consensus of response, suggesting influence by multiple parameters, such as particle type, particle energy, and tumor type. Systematic gene expression studies can help to address these issues, and promoting a culture of data sharing will expedite the process, benefiting investigators across the radiation therapy field.

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Expression of Genes Involved in Mouse Lung Cell Differentiation/Regulation after Acute Exposure to Photons and Protons with or without Low-Dose Preirradiation

Cited by 18 publications

References 45 publications

Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma

Gene Expression Studies for the Development of Particle Therapy

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