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At least 19 recordsLinked to original sources
PubMed2006

Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect.

Radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the final biological consequences of exposure to low doses of radiation. Evidence suggests that targeted cytoplasmic irradiation results in mutation in the nucleus of the "hit" cells and that cells, which are not directly hit by an alpha particle, whether nuclear or cytoplasm, but are in the vicinity of one that does get hit, contribute to the genotoxic response of the cell population. Although radiation-induced bystander effects have been well documented in a variety of biological systems, the mechanism is not known. Using the Columbia University charged particle beam in conjunction with a novel strip dish design, we showed recently that the cyclooxygenase-2 (COX-2) signaling cascade plays an essential role in the bystander process. Treatment of bystander cells with NS-398, which suppresses COX-2 activity, significantly reduced the bystander effect as well as the induction of the mitogen-activated protein kinase (MAPK) pathways. These results provided the first evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory responses, is the critical signaling link for the bystander phenomenon. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon together with evidence of their occurrence in vivo will allow us to formulate a more accurate model in assessing the health effects of low doses of ionizing radiation.

Animals↗
PubMed2002

Computer modelling of radiation-induced bystander effect.

Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be aprotein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles.

Bystander Effect↗
PubMed2006

High-LET ion radiolysis of water: visualization of the formation and evolution of ion tracks and relevance to the radiation-induced bystander effect.

Ionizing radiation-induced bystander effects, commonly observed in cell populations exposed to high-linear energy transfer (LET) radiations, are initiated by damage to a cellular molecule which then gives rise to a toxic signal exported to neighboring cells not directly hit by radiation. A major goal in studies of this phenomenon is the identification of this initial radiation-induced lesion. Liquid water being the main constituent of biological matter, reactive species produced by water radiolysis in the cellular environment are likely to be major contributors to the induction of this lesion. In this context, the radiation track structure is of crucial importance in specifying the precise location and identity of all the radiolytic species and their subsequent signaling or damaging effects. We report here Monte Carlo track structure simulations of the radiolysis of liquid water by four different impacting ions 1H+, 4He2+, 12C6+ and 20Ne10+, with the same LET ( approximately 70 keV/ microm). The initial radial distribution profiles of the various water decomposition products (eaq(-), *OH, H*, H2 and H2O2) for the different ions considered are presented and discussed briefly in the context of track structure theory. As an example, the formation and temporal evolution of simulated 24 MeV 4He2+ ion tracks (LET approximately 26 keV/microm) are reported for each radiolytic species from 1 ps to 10 micros. The calculations reveal that the ion track structure is completely lost by approximately 1 micros.

Bystander Effect↗
PubMed2004

Radiotherapy and the potential exploitation of bystander effects.

Radiation-induced bystander effects are the subject of intense investigation in radiation protection. The effects predominate at low doses and have been discussed mainly in terms of the impact on low-dose risk assessment. Possible therapeutic implications have been alluded to, but not discussed in any detail. The purpose of this review was to consider bystander biology in areas of major importance or interest in radiotherapy. These include consideration of radiation-induced bystander effects during the cell cycle, under hypoxic conditions, when fractionated therapy modalities are used, or when combined radiochemotherapy is given. Also discussed are individual variations in toxicity of bystander factors and normal tissue "collateral" damage. The importance of considering the tumor in the context of the organ, and even the organism that supports it, is also discussed. Direct clinical radiotherapy studies that consider bystander effects are not in the public domain at the time of writing, but many in vitro studies are available that are relevant; some preliminary animal data have also been published. Because radiation-induced bystander effects appear to challenge many of the central assumptions that underlie radiotherapy practice, it is important to consider what unexplored treatment avenues might result from a consideration of these effects. The final part of this paper is devoted to this point.

Bystander Effect↗
PubMed2003

Biophysical model of the radiation-induced bystander effect.

PURPOSE: To construct a quantitative model of the radiation-induced bystander effect based on diffusion-type spreading of bystander signal communication between the hit and non-hit cells. Cell inactivation and induced oncogenic transformation by broad- and microbeam irradiation systems are considered. MATERIALS AND METHODS: The biophysical model ByStander Diffusion Modelling (BSDM) postulates that the oncogenic bystander response observed in non-hit cells originates from specific signals received from inactivated cells. The bystander signals are assumed to be protein-like molecules spreading in the culture media by Brownian motion. The bystander signals are assumed to switch cells into a state of cell death (apoptotic/mitotic/necrosis) or induced oncogenic transformation modes. RESULTS: The bystander cell survival observed after treatment with the irradiated conditioned medium (ICM) using the broad-beam and the microbeam irradiation modalities were analysed and interpreted in the framework of the BSDM model. The model predictions for cell inactivation and induced oncogenic transformation frequencies agree well with observed data from micro and broad-beam experiments. In the case of irradiation with constant fraction of cells, transformation frequency for the bystander effect increases with increasing radiation dose. CONCLUSIONS: Bystander modelling based on diffusion of signals is in good agreement with experimental cell survival data and induced oncogenic transformation frequencies. The data confirm the protein-like nature of the bystander signal. Linear extrapolation of the cell response to low doses of radiation might underestimate carcinogenic risk, for example for domestic radon hazards, if the contribution from the bystander effect is neglected. The BSDM predicts that the bystander effect cannot be interpreted solely as a low-dose effect phenomenon. It is shown that the bystander component of radiation response can increase with dose and be observed at high doses as well as at low doses. The validity of this conclusion is supported by analysis of experimental results from high-linear energy transfer microbeam experiments.

Alpha Particles↗
PubMed2005

Differential impact of mouse Rad9 deletion on ionizing radiation-induced bystander effects.

The cellular response to ionizing radiation is not limited to cells irradiated directly but can be demonstrated in neighboring "bystander" populations. The ability of mouse embryonic stem (ES) cells to express a bystander effect and the role of the radioresistance gene Rad9 were tested. Mouse ES cells differing in Rad9 status were exposed to broad-beam 125 keV/ microm 3He alpha particles. All populations, when confluent, demonstrated a dose-independent bystander effect with respect to cell killing, and the Rad9-/- genotype did not selectively alter that response or cell killing after direct exposure to this high-LET radiation. In contrast, relative to Rad9+/+ cells, the homozygous mutant was sensitive to direct exposure to alpha particles when in log phase, providing evidence of a role for Rad9 in repair of potentially lethal damage. Direct exposure to alpha particles induced an increase in the frequency of apoptosis and micronucleus formation, regardless of Rad9 status, although the null mutant showed high spontaneous levels of both end points. All populations demonstrated alpha-particle-induced bystander apoptosis, but that effect was most prominent in Rad9-/- cells. Minimal alpha-particle induction of micronuclei in bystander cells was observed, except for the Rad9-/- mutant, where a significant increase above background was detected. Therefore, the Rad9 null mutation selectively sensitizes mouse ES cells to spontaneous and high-LET radiation-induced bystander apoptosis and micronucleus formation, but it has much less impact on cell killing by direct or bystander alpha-particle exposure. Results are presented in the context of defining the function of Rad9 in the cellular response to radiation and its differential effects on individual bystander end points.

Alpha Particles↗
PubMed2006

The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects.

Much evidence now exists regarding radiation-induced bystander effects, but the mechanisms involved in the transduction of the signal are still unclear. The mitogen-activated protein kinase (MAPK) pathways have been linked to growth factor-mediated regulation of cellular events such as proliferation, senescence, differentiation and apoptosis. Activation of multiple MAPK pathways such as the ERK, JNK and p38 pathways have been shown to occur after exposure of cells to radiation and a variety of other toxic stresses. Previous studies have shown oxidative stress and calcium signaling to be important in radiation-induced bystander effects. The aim of the present study was to investigate MAPK signaling pathways in bystander cells exposed to irradiated cell conditioned medium (ICCM) and the role of oxidative metabolism and calcium signaling in the induction of bystander responses. Human keratinocytes (HPV-G cell line) were irradiated (0.005-5 Gy) using a cobalt-60 teletherapy unit. The medium was harvested 1 h postirradiation and transferred to recipient HPV-G cells. Phosphorylated forms of p38, JNK and ERK were studied by immunofluorescence 30 min-24 h after exposure to ICCM. Inhibitors of the ERK pathway (PD98059 and U0126), the JNK pathway (SP600125), and the p38 pathway (SB203580) were used to investigate whether bystander-induced cell death could be blocked. Cells were also incubated with ICCM in the presence of superoxide dismutase, catalase, EGTA, verapamil, nifedipine and thapsigargin to investigate whether bystander effects could be inhibited because of the known effects on calcium homeostasis. Activated forms of JNK and ERK proteins were observed after exposure to ICCM. Inhibition of the ERK pathway appeared to increase bystander-induced apoptosis, while inhibition of the JNK pathway appeared to decrease apoptosis. In addition, reactive oxygen species, such as superoxide and hydrogen peroxide, and calcium signaling were found to be important modulators of bystander responses. Further investigations of these signaling pathways may aid in the identification of novel therapeutic targets.

Bystander Effect↗
PubMed2004

The radiation-induced bystander effect: evidence and significance.

A multitude of biological effects observed over the past two decades in various in vivo and in vitro cell culture experiments have indicated that low dose/low fluence ionizing radiation has significantly different biological responses than high dose radiation. Exposure of cell populations to very low fluences of alpha-particles or incorporated radionuclides results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. Cells recipient of growth medium from irradiated cultures can also respond to the radiation exposure. This phenomenon, termed the 'bystander response', has been postulated to impact both the estimation of risks of exposure to ionizing radiation and radiotherapy. Amplification of radiation-induced cytotoxic and genotoxic effects by the bystander effect is in contrast to the observations of adaptive responses, which are generally induced following exposure to low dose, low linear energy transfer radiation and which tend to attenuate radiation-induced damage. In this article, the evidence for existence of radiation-induced bystander effects and our current knowledge of the biochemical and molecular events involved in mediating these effects are described. Potential similarities between factors that mediate the radiation-induced bystander and adaptive responses are highlighted.

Alpha Particles↗
PubMedDate not supplied

Genomic instability, bystander effects and radiation risks: implications for development of protection strategies for man and the environment.

The last few years has seen what people are now referring to as a "shifting Paradigm" in our way of thinking about radiation effects on biological systems. The concept of the central role of DNA damage due to double strand breaks induced by a radiation "hit" has been itself hit by many studies showing persistent effects in the distant progeny of radiation exposed cells. This phenomenon is known as radiation induced genomic instability. More recently evidence has been accumulating that not even the parent cell need be exposed to radiation (the bystander effect). The new paradigm suggests that cellular stress responses or damage signalling through a range of signal transduction pathways are involved and that cell-cell contact or secretion of damage signalling molecules can induce responses in undamaged and unirradiated cells. Are these new effects relevant to risk assessment, or does it matter HOW radiation affects cells if we have good epidemiological evidence of which to base our risk estimates? The aim of this paper is to introduce the new concepts and to consider reasons why they might alter our methods of risk estimation. The paper also considers the impact of the new concepts on environmental protection and discusses the need for research in the field of comparative radiobiology if we are to develop policies which can adequately protect biodiversity.

Animals↗
PubMed2006

Non-targeted bystander effects induced by ionizing radiation.

Radiation-induced bystander effects refer to those responses occurring in cells that were not subject to energy deposition events following ionizing radiation. These bystander cells may have been neighbors of irradiated cells, or physically separated but subject to soluble secreted signals from irradiated cells. Bystander effects have been observed in vitro and in vivo and for various radiation qualities. In tribute to an old friend and colleague, Anthony V. Carrano, who would have said "well what are the critical questions that should be addressed, and so what?", we review the evidence for non-targeted radiation-induced bystander effects with emphasis on prevailing questions in this rapidly developing research field, and the potential significance of bystander effects in evaluating the detrimental health effects of radiation exposure.

Animals↗
PubMed2006

Cellular radiation effects and the bystander response.

This report reviews briefly some of the findings reported over the past 2 years that enhance our understanding of the radiation-induced bystander effect. These developments include: technicological advances; the role of oxidative stress; the effect of cytoplasmic irradiation; cell-to-cell communication; and evidence that Connexin 43 mediated intercellular communication is induced by radiation exposure. A few overriding unanswered questions are discussed. These include: what is the signal(s) transmitted from irradiated to bystander cells; what is the relationship between the bystander response and other non-targeted effects of radiation; are there beneficial effects associated with the bystander response; and what is the significance of the bystander effect for radiation protection?

Animals↗
PubMed2005

The time and spatial effects of bystander response in mammalian cells induced by low dose radiation.

Bystander effects induced by low dose of ionizing radiation have been shown to widely exist in many cell types and may have a significant impact on radiation risk assessment. Though many studies have been reported on this phenomenological observation, the mechanisms underlying this process are not clear, especially on the questions of how soon after irradiation the bystander effects can be initiated and how far this bystander signal can be propagated once it is started. DNA double-strand breaks (DSBs) induced by ionizing radiation or carcinogenic chemicals can be visualized in situ using gamma-H2AX immunofluorescent staining. Our previous studies have shown that in situ visualization of DSBs could be used to assess irradiation-induced extranuclear/extracellular (bystander) effect at an early stage after irradiation. In the present studies, we used this method to investigate the time and spatial effects of damage signals on unirradiated bystander cells. The results showed that increased DSBs in irradiated and unirradiated bystander areas could be visualized 2 min after radiation and reached its maximum 30 min after radiation. The average levels of DSB formation at 30 min post-1cGy irradiation in the irradiated and unirradiated bystander areas were 3-fold and 2-fold higher than those of the sham-irradiated control cells, respectively. Afterwards, the formation of DSBs declined with incubation time and remained steady for at least 6 h at a level that was statistically higher than their controls. The results also showed that the bystander signal derived from irradiated cells could be transferred to anywhere in the dish and the percentage of DSBs in the unirradiated bystander cells was not dependent on the dose delivered. Moreover, the fraction of DSB positive cells in unirradiated bystander areas showed a time-dependent increase based on its distance to the irradiated area at very early stage post-irradiation. Both lindane and DMSO significantly suppressed the yield of DSBs in the cells of unirradiated bystander areas, which suggest that gap junctional intercellular communication and reactive oxygen species played important roles in the induction of the bystander effects, both in irradiated and unirradiated bystander areas.

Bystander Effect↗
PubMed2003

Radiation-induced bystander effects, carcinogenesis and models.

Implications for carcinogenesis of radiation-induced bystander effects are both mechanistic and practical. They include induction of second cancers, perturbations to tissue social control and induction of genomic instability and delayed or immediate mutations in areas not receiving a direct deposition of energy. Bystander effects have consequences for DNA damage-mutation-cancer initiation paradigms of radiation carcinogenesis that provide the mechanistic justification for low-dose risk estimates. If carcinogenesis does not result from directly induced DNA mutations, then the carcinogenic initiation process may not simply relate to radiation dose. Modification of the preclonal state through genetic and epigenetic mechanisms may occur. To deal with the complexity of these interactions, a 'chaotic' or 'bifurcation' model invoking autopoietic theory is proposed that could accommodate both beneficial (hormetic) and harmful effects of radiation at comparable doses. Carcinogenesis may then be thought of as the result of a disturbance of the genetic/epigenetic balance occurring within the organ. Ultimate clonality may reflect domination due to selection processes rather than the initiating damage.

Animals↗
PubMed2001

Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects?

Haemopoietic tissues exposed to ionizing radiation are shown to exhibit increased macrophage activation, defined by ultrastructural characteristics and increased lysosomal and nitric oxide synthase enzyme activities. Macrophage activation post-irradiation was also associated with enhanced respiratory burst activities and an unexpected neutrophil infiltration. Examination of p53-null mice demonstrated that macrophage activation and neutrophil infiltration were not direct effects of irradiation, but were a consequence of the recognition and clearance of radiation-induced apoptotic cells. Increased phagocytic cell activity was maintained after apoptotic bodies had been removed. These findings demonstrate that, contrary to expectation, recognition and clearance of apoptotic cells after exposure to radiation produces both a persistent macrophage activation and an inflammatory-type response. We also demonstrate a complexity of macrophage activation following radiation that is genotype dependent, indicating that the in vivo macrophage responses to radiation damage are genetically modified processes. These short-term responses of macrophages to radiation-induced apoptosis and their genetic modification are likely to be important determinants of the longer-term consequences of radiation exposure. Furthermore, in addition to any effects attributable to immediate radiation-induced damage, our findings provide a mechanism for the production of damage via a 'bystander' effect which may contribute to radiation-induced genomic instability and leukaemogenesis.

Animals↗
PubMed2005

Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway.

The radiation-induced bystander effect is defined as "the induction of biological effects in cells that are not directly traversed by a charged particle but are in close proximity to cells that are." Although these bystander effects have been demonstrated with a variety of biological endpoints in both human and rodent cell lines (as well as in 3D tissue samples), the mechanism of the phenomenon is not known. Although gap junction communication and the presence of soluble mediator(s) are both known to play important roles in the bystander response, the precise signaling molecules have yet to be identified. By using the Columbia University charged particle beam in conjunction with a strip dish design, we show here that the cyclooxygenase-2 (COX-2, also known as prostaglandin endoperoxide synthase-2) signaling cascade plays an essential role in the bystander process. Treatment of bystander cells with NS-398, which suppresses COX-2 activity, significantly reduced the bystander effect. Because the critical event of the COX-2 signaling is the activation of the mitogen-activated protein kinase pathways, our finding that inhibition of the extracellular signal-related kinase phosphorylation suppressed bystander response further confirmed the important role of mitogen-activated protein kinase signaling cascade in the bystander process. These results provide evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory response, is the critical signaling link for the bystander phenomenon.

Alpha Particles↗
PubMed2001

Radiation-induced bystander effects: past history and future directions.

There has been a recent upsurge of interest in the phenomenon now known as radiation-induced bystander effects. This is largely due to the increased awareness of the contribution of indirect and delayed effects, such as genomic instability, to cellular outcomes after low-dose exposures. It is also due to the availability of tools such as the microbeam and advanced cell culture systems and to the ability to study end points such as gene or protein expression at low doses which were previously difficult to study. This review looks at the history of bystander effects in the earlier literature, in which the clastogenic effect of plasma from irradiated patients was well known. The effect was known to persist for several years and to cause transgenerational effects, making it similar to what we now call genomic instability. The review then examines the current data and controversies which are now beginning to resolve the questions concerning the mechanisms underlying the induction and transmission of both bystander effects and genomic instability. Finally, the possible impact of data concerning radiation-induced bystander effects on radiotherapy and radiation protection is discussed.

Animals↗
PubMed2004

Radiation-induced bystander effect in immune response.

OBJECTIVE: Since most reports on bystander effect have been only concerned with radiation-induced damage, the present paper aimed at disclosing whether low dose radiation could induce a stimulatory or beneficial bystander effect. METHODS: A co-culture system containing irradiated antigen presenting cells (J774A.1) and unirradiated T lymphocytes (EL-4) was established to observe the effect of J774A.1 cells exposed to both low and high doses of X-rays on the unirradiated EL-4 cells. Incorporation of 3H-TdR was used to assess the proliferation of the EL-4 cells, expression of CD80/86 and CD48 on J774A.1 cells was measured with immunohistochemistry and flow cytometry, respectively. NO release from J774A.1 cells was estimated with nitrate reduction method. RESULTS: Low dose-irradiated J774A.1 cells could stimulate the proliferation of the unirradiated EL-4 cells while the high dose-irradiated J774A.1 cells exerted an inhibitory effect on the proliferation of the unirradiated EL-4 cells. Preliminary mechanistic studies illustrated that the differential changes in CD48 expression and NO production by the irradiated J774A.1 cells after high and low dose radiation might be important factors underlying the differential bystander effect elicited by different doses of radiation. CONCLUSION: Stimulatory bystander effect can be induced in immune cells by low dose radiation.

Animals↗
PubMed2004

Review of radiation-induced bystander effects.

It is now apparent that the target for the biological effects of ionizing radiation (IR) is not solely the irradiated cell(s), but also includes the surrounding cells/tissue as well. Radiation-induced bystander effects (BSEs) are defined by the presence of the biological effects of radiation in cells that were not themselves in the field of irradiation. Decreased plating efficiency, increased sister chromatid exchanges, oncogenic transformation, among other endpoints have been used to describe the BSE. Two primary means have been established for the transmission of the bystander signal; one is mediated by gap-junction intracellular communication, and the other is initiated through the secretion of factors from irradiated cells. While the basis for these phenomena have been established in cell culture systems, there is also evidence for their presence in vivo. This in vivo effect may contribute to increased tumor cell killing, and may also play a role in the abscopal effects of radiation, where radiation responses are seen in areas separated from the irradiated tissue. Although the precise molecular components and mechanisms remain unknown, their discovery will shed new light on the role of the BSEs in radiation risk assessment, and clinical radiotherapy in the clinic.

Animals↗