Radiation-Induced Bystander Effects, Carcinogenesis and Models

Oncogene (2003) 22, 7028–7033 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Radiation-induced bystander effects, carcinogenesis and models Carmel Mothersill*,w,1 and Colin Seymour1,2 1Radiation and Environmental Science Center, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland; 2Saint Luke’s Institute of Cancer Research, Highfield Road, Rathgar, Dublin 6, Ireland Implications for carcinogenesis of radiation-induced by- ability, result in a cell being ‘initiated’ due to mutation at stander effects are both mechanistic and practical. They a critical site. This can be followed by promotion and include induction of second cancers, perturbations to progression of an essentially clonal population. Radia- tissue social control and induction of genomic instability tion is assumed only to be involved in initiation. The new and delayed or immediate mutations in areas not receiving position that many suggest is necessary in order to a direct deposition of energy. Bystander effects have accommodate both bystander effects and genomic consequences for DNA damage-mutation-cancer initiation instability is that the multiple-step carcinogenic process paradigms of radiation carcinogenesis that provide the is mediated from the start and throughout, by epigenetic mechanistic justification for low-dose risk estimates. If and indirect effects of radiation. A major pillar of this carcinogenesis does not result from directly induced DNA proposed paradigm shift is that bystander effects induced mutations, then the carcinogenic initiation process may by radiation in nonexposed cells actually drive the not simply relate to radiation dose. Modification of the process of genomic instability and that this genomic preclonal state through genetic and epigenetic mechanisms instability both precedes and facilitates the evolution of may occur. To deal with the complexity of these clonal (potentially carcinogenic) mutations. interactions, a ‘chaotic’ or ‘bifurcation’ model invoking In the target theory paradigm, all radiation events autopoietic theory is proposed that could accommodate were contained in the ‘hit’ cell. There was a direct energy both beneficial (hormetic) and harmful effects of radiation deposition leading to DNA damage. In this paradigm, at comparable doses. Carcinogenesis may then be thought only the cell directly exposed to radiation could suffer of as the result of a disturbance of the genetic/epigenetic any damage. The changing paradigm, by including balance occurring within the organ. Ultimate clonality downstream effects occurring in cells not directly may reflect domination due to selection processes rather exposed to radiation, but receiving damage signals from than the initiating damage. irradiated cells, allows cell–cell and cell–matrix commu- Oncogene (2003) 22, 7028–7033. doi:10.1038/sj.onc.1206882 nication to be involved. Implicit in this changing paradigm is a change in target size, making large Keywords: radiation; carcinogenesis; bystander effects; interaction distances and longer times of interaction chaos models; social evolution; autopoietic theory relevant. While the bystander factor(s) has not yet been identified, the existence of this signalling mechanism, at least theoretically, allows the damage signal production resulting from dose deposition to be distinguished from Introduction the cellular response. This introduces a multidimen- sional context to radiation carcinogenesis where spatial Radiation-induced bystander effects have been widely and temporal parameters, and responses of recipient reviewed in the literature (Mothersill and Seymour, 2001; cells are as important as dose. Goldberg and Lehnert, 2002; Lorimore and Wright, The measured end points of cellular bystander 2003; Morgan 2003a, b; Mothersill and Seymour, 2003), response have been mutation, gene induction, micro- and refer to effects detected in cells that were not directly nuclei formation, cell transformation and cell killing (see ‘hit’ by an ionizing radiation track. This paper is reviews cited above). These are similar to those intended to discuss the implications of these effects in measured for genomic instability and again demonstrate the carcinogenic process and to discuss whether they the close association between the two phenomena. The require a paradigm shift in the radiation carcinogenesis demonstrated existence of a high frequency of nonclonal field from the existing position involving, essentially, the mutations in postirradiation populations of cells, which hit (target) theory, where DNA damage is seen as is characteristic of genomic instability alters the resulting from random hits to the chemical structure of established single-cell, multiple-step paradigm of carci- DNA which can, with a definable dose-related prob- nogenesis towards a model postulating tissue interactions and responses interfacing with instability to facilitate cancer formation. This is a vastly more *Correspondence: Dr C Mothersill; E-mail: [email protected] w - Current address: McMaster University, Dept Medical Physics and complex situation than the simple ‘dose DNA Applied Radiation Science, Hamilton, Ontario, Canada break-mutation’ theory. Bystander effects and carcinogenesis C Mothersill and C Seymour 7029 The single cell mutation theory of radiation-induced 1992; Loeb, 2001). Thus it is reasonable to postulate cancer suggests that the tumour arises through stages of that the initial change is epigenetically induced and is initiation, promotion and progression. The initial sustained by cell–cell communication or environmental mutation caused by radiation is a rare and stochastic factors. Epigenetic effects can be defined as causing event. In contrast, a genomic instability theory would mitotically heritable changes in gene expression that are suggest a common event cause, with gene mutation not caused by an alteration of the DNA sequence. occurring frequently, but being controlled through cell– Methylation changes are an example and there is cell communication-mediated processes involving by- evidence of methylation changes following exposure of stander signals and responses. Only if the epigenetic cells to bystander signals (Grandjean et al., submitted). control breaks down does progression to cancer occur. A distinction between an epigenetic mechanism and a This model also allows a reversibility after radiation genetic mechanism is that epigenetic changes are exposure, not available in the initiation, promotion and chemically reversible. These epigenetic influences can progression model. occur from different cells or tissues, or can occur after a Bystander effects and genomic instability are both lapse in time from the original radiation event. induced at very low doses. To use environmental In Figure 1, the options that a cell population exposed toxicology jargon, no doses corresponding to no either to direct irradiation or bystander signals could observable effect level (NOEL) or lowest observable face are shown schematically. Rather than adhere to an effect level (LOEL) have yet been defined. The lowest initiation, promotion and progression model which is so doses used (one alpha particle track to one cell in a strongly identified with the DNA damage-centred population or 2 mGy gamma radiation to a population paradigm, we have conceptualized induction, fixation of cells) caused the same amount of genomic instability and expression stages in the evolution of a cancer where or other bystander end point as doses that were orders tissue processes can influence outcome both before and of magnitude higher (Seymour and Mothersill, 2000; after fixation of DNA damage. Kadhim et al., 2001; Ostreicher et al., 2003) Tradition- There is a wealth of evidence related to the fact that ally, radiation protection authorities have combined many tumours do have a clonal origin (or perhaps more target theory with the single cell initiation, promotion accurately an early clonal mutation) and a distinct and progression model to predict a linear reduction of identifiable genetic fingerprint (Noguchi et al., 1995; carcinogenic effect with decreasing radiation dose. Bedi et al., 1996; Werness et al., 1997). However, it is Bystander and genomic instability effects introduce a generally impossible to know what level of variability nonlinearity into the low-dose area, where the response existed before the emergence of clonality and whether of the tissue/cell population rather than the doses will this is a secondary consequence of selection events determine the fate of the cell and ultimately, the occurring very early in the evolution of the altered state. organism. Given the complexity and variety of cellular It is our hypothesis that once a clonal event has interactions and the randomness of radiation damage, occurred, that is, a direct heritable DNA mutation, whether direct or bystander-induced, we have consi- then it is ‘committed’ or ‘fixed’ and cannot be reversed dered whether this response is predictable or whether it through epigenetic mechanisms. In terms of a general is essentially chaotic. chaotic model, the myriad of constant chemical interactions within a cell are essentially chaotic. The change in DNA status (through mutation) could then be Clonality of tumours, bystander effects and genomic instability Options and choices for exposed cell populations There is evidence that bystander signals can induce Affected cells I induction genomic instability both in vivo (Watson et al., 2000; Live with Lorimore et al., 2001) and in vitro

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