Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation

Desai, Sejal; Kobayashi, Adam; Konishi, Teruaki; Oikawa, Masakazu; Pandey, Badri N.

doi:10.1016/j.mrfmmm.2014.03.004

Cited by 49 publications

(62 citation statements)

References 17 publications

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“…Our results, using modulation periods of 5.0 and 2.5 mm, show that the biological response is sensitive to the period of modulation in this region. Positive and negative bystander effects have been described in the literature, with various signaling mechanisms suggested [17,29]. The extent and complexity of non-targeted bystander effects highlight the involvement of multiple factors, including the system under study (cell type).…”

Section: Discussionmentioning

confidence: 99%

“…Medium mediated signaling involves the release of soluble factors that diffuse through the medium, inducing biological effects in unirradiated cells. Studies of bystander effects have reported both protective and damaging bystander responses, which encourage cell proliferation and cell death respectively [16,17], depending on the dose, dose rate, cell type [16,[18][19][20] and spatial and temporal modulation [21]. The extent of bystander effects on survival is known to be cell specific and proportional to the dose received, saturating at higher doses where direct effects of radiation dominate [18,19].…”

Section: Bystander Effectmentioning

confidence: 99%

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Grid therapy using high definition multileaf collimators: realizing benefits of the bystander effect

et al. 2017

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Relative to an open field, survival of normal cells in a 2.5 mm striped field was the same, while the survival of both cancer cell lines was significantly lower. A mathematical model was developed to incorporate dose gradients of the spatial modulation into the standard linear quadratic model. Our new bystander extended LQ model assumes spatial gradients drive the diffusion of soluble factors that influence survival through bystander effects, successfully predicting the experimental results that show an increased therapeutic ratio. Our results challenge conventional radiotherapy practice and propose that additional gain can be realized by prescribing spatially modulated treatments to harness the bystander effect.

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Section: Discussionmentioning

confidence: 99%

Section: Bystander Effectmentioning

confidence: 99%

Grid therapy using high definition multileaf collimators: realizing benefits of the bystander effect

et al. 2017

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“…The secretion of signaling factors of this particular cellular response can also protect cells from further damages by preenhancing repair mechanisms or lead to a faster clean-up of radiation-damaged cells (40–42). …”

Section: Radiation-induced Bystander Effectsmentioning

confidence: 99%

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

Diegeler

Hellweg

2017

Front. Immunol.

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Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

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“…Conditioned media transfer [8, 9], microbeam [10] and tissue culture inserts [11] have been commonly used to demonstrate RIBE in various cancer cell lines pertaining to cancer radiotherapy. Although these experimental approaches have provided significant understanding about signaling mechanisms and kinetics of RIBE, they do not accurately represent the physiological conditions and multi-cellular tumor environment [12].…”

Section: Introductionmentioning

confidence: 99%

Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

Desai¹,

Nishad²,

Yadav³

et al. 2016

PLoS ONE

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Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about the damaging RIBE in an in vivo tumor model, which may have significant implication in improvement of cancer radiotherapy.

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Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation

Cited by 49 publications

References 17 publications

Grid therapy using high definition multileaf collimators: realizing benefits of the bystander effect

Grid therapy using high definition multileaf collimators: realizing benefits of the bystander effect

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

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