Rescue effects in radiobiology: Unirradiated bystander cells assist irradiated cells through intercellular signal feedback

Chen, Songying; Zhao, Yang; Han, Wei; Chiu, Sung-Kay; Zhu, Lingyan; Wu, Lijun; Yu, K.N.

doi:10.1016/j.mrfmmm.2010.10.011

Cited by 68 publications

(88 citation statements)

References 24 publications

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“…Therefore, the cells exposed to low-LET δ rays may experience up-regulation of protective rather than damaging effects, and could attenuate the damaging effects propagated from cells traversed by primary energetic neon or argon particles (41). Conversely, truly bystander cells in the exposed population may also transmit rescuing signals to the irradiated cells (51, 52). Therefore, the overall response of the cell population depends not only on the pattern of energy deposition (53), but also on the extensive network of intercellular communication between targeted and nontargeted cells.…”

Section: Discussionmentioning

confidence: 99%

Gap Junction Communication and the Propagation of Bystander Effects Induced by Microbeam Irradiation in Human Fibroblast Cultures: The Impact of Radiation Quality

Autsavapromporn¹,

Suzuki²,

Funayama

et al. 2013

Radiation Research

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Understanding the mechanisms underlying the bystander effects of low doses/low fluences of low- or high-linear energy transfer (LET) radiation is relevant to radiotherapy and radiation protection. Here, we investigated the role of gap-junction intercellular communication (GJIC) in the propagation of stressful effects in confluent normal human fibroblast cultures wherein only 0.036–0.144% of cells in the population were traversed by primary radiation tracks. Confluent cells were exposed to graded doses from monochromatic 5.35 keV X ray (LET ~6 keV/μm), 18.3 MeV/u carbon ion (LET ~103 keV/μm), 13 MeV/u neon ion (LET ~380 keV/μm) or 11.5 MeV/u argon ion (LET ~1,260 keV/μm) microbeams in the presence or absence of 18-α-glycyrrhetinic acid (AGA), an inhibitor of GJIC. After 4 h incubation at 37°C, the cells were subcultured and assayed for micronucleus (MN) formation. Micronuclei were induced in a greater fraction of cells than expected based on the fraction of cells targeted by primary radiation, and the effect occurred in a dose-dependent manner with any of the radiation sources. Interestingly, MN formation for the heavy-ion microbeam irradiation in the absence of AGA was higher than in its presence at high mean absorbed doses. In contrast, there were no significant differences in cell cultures exposed to X-ray microbeam irradiation in presence or absence of AGA. This showed that the inhibition of GJIC depressed the enhancement of MN formation in bystander cells from cultures exposed to high-LET radiation but not low-LET radiation. Bystander cells recipient of growth medium harvested from 5.35 keV X-irradiated cultures experienced stress manifested in the form of excess micronucleus formation. Together, the results support the involvement of both junctional communication and secreted factor(s) in the propagation of radiation-induced stress to bystander cells. They highlight the important role of radiation quality and dose in the observed effects.

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Section: Discussionmentioning

confidence: 99%

Gap Junction Communication and the Propagation of Bystander Effects Induced by Microbeam Irradiation in Human Fibroblast Cultures: The Impact of Radiation Quality

Autsavapromporn¹,

Suzuki²,

Funayama

et al. 2013

Radiation Research

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“…In addition, it has been reported that the bystander cells can also alleviate the DNA damages in the hit cells through the rescue effect. [26][27][28] So, an interesting question arises whether bystander root tips can affect the course of bystander signaling in irradiated root region. To clarify this, a 3mm long region of root tip was removed immediately before or the bystander signaling along roots might be of directionality.…”

Section: The Effect Of Removal Of Root Tips On the Course Of Bystandementioning

confidence: 99%

“…37 Interestingly, the bystander cells were recently shown to alleviate the DNA damages and cell apoptosis in hit cells through the rescue effect. [26][27][28] Some evidence showed that the DNA damage is important for the generation of bystander signals in hit cells, as the bystander signals from DNA repair deficient cells are more toxic. 38,39 Thus, the bystander cells should irradiation or the upstream signaling events activated by these signals in bystander tissues might persist a relatively shorter time than those within 0-4 h after irradiation.…”

Section: The Effect Of Removal Of Aerial Plants On the Course Of Bystmentioning

confidence: 99%

Novel features of radiation-induced bystander signaling in Arabidopsis thaliana demonstrated using root micro-grafting

Wang

et al. 2012

Plant Signaling & Behavior

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Radiation-induced bystander effects (RIBE) have been well demonstrated in whole organisms, as well as in single-cell culture models in vitro and multi-cellular tissues models in vitro, however, the underlying mechanisms remain unclear, including the temporal and spatial course of bystander signaling. The RIBE in vivo has been shown to exist in the model plant Arabidopsis thaliana (A. thaliana). Importantly, the unique plant grafting provides a delicate approach for studying the temporal and spatial course of bystander signaling in the context of whole plants. In our previous study, the time course of bystander signaling in plants has been well demonstrated using the root micro-grafting technique. In this study, we further investigated the temporal cooperation pattern of multiple bystander signals, the directionality of bystander signaling, and the effect of bystander tissues on the bystander signaling. The results showed that the bystander response could also be induced efficiently when the asynchronously generated bystander signals reached the bystander tissues in the same period, but not when they entered into the bystander tissues in an inversed sequence. The absence of bystander response in root-inversed grafting indicated that the bystander signaling along roots might be of directionality. The bystander signaling was shown to be independent of the bystander tissues.

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“…Recently, radiation-induced bystander cells were shown to rescue irradiated cells through intercellular feedback. Chen et al [40] observed a significant decrease in the number of DNA double-strand breaks, micronuclei frequencies, and the extent of apoptosis in irradiated cells that were co-cultured with unirradiated bystander cells. Observation of an absence of a bystander effect in the present study may help explain the sensitivity of radioresistant tumor cells to neutrons, because there is a possibility that the protection otherwise provided by the bystander effect on the tumor in response to neutrons is absent or not strong enough in magnitude, thereby causing tumor cells to be killed.…”

Section: Discussionmentioning

confidence: 99%

“…Depending upon the cell and tissue type, bystander signals can be transmitted either through the culture medium [17] or by cell-to-cell contact including gap junctional communication [37]. Some of the candidate intercellular signaling molecules that have been implicated in bystander effects are reactive oxygen species [20], [38], reactive nitrogen species [20], [38], nitric oxide [27], [38], cytokines such as TGFβ and interleukin 8 [39], and small molecules such as amino acids [37], [40], [41]. The involvement of intracellular signaling molecules including mitogen-activated protein kinases (MAPK) and their downstream proteins [42], [43], protein kinase C (PKC) isoforms [44], tumor protein 53 (p53) [45], [46], cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) [47], ataxia telangiectasia mutated protein (ATM) [44], and ataxia telangiectasia and Rad3 related (ATR) DNA-dependent protein kinase (DNA-PK) [44], [48] have also been implicated.…”

Section: Introductionmentioning

confidence: 99%

Neutron Exposures in Human Cells: Bystander Effect and Relative Biological Effectiveness

et al. 2014

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Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (p<0.0001). These data indicate that neutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0±0.13 for micronuclei and 5.8±2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.

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Rescue effects in radiobiology: Unirradiated bystander cells assist irradiated cells through intercellular signal feedback

Cited by 68 publications

References 24 publications

Gap Junction Communication and the Propagation of Bystander Effects Induced by Microbeam Irradiation in Human Fibroblast Cultures: The Impact of Radiation Quality

Gap Junction Communication and the Propagation of Bystander Effects Induced by Microbeam Irradiation in Human Fibroblast Cultures: The Impact of Radiation Quality

Novel features of radiation-induced bystander signaling in Arabidopsis thaliana demonstrated using root micro-grafting

Neutron Exposures in Human Cells: Bystander Effect and Relative Biological Effectiveness

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