Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away

Abstract

A central tenet in understanding the biological effects of ionizing radiation has been that the initially affected cells were directly damaged by the radiation. By contrast, evidence has emerged concerning ''bystander'' responses involving damage to nearby cells that were not themselves directly traversed by the radiation. These long-range effects are of interest both mechanistically and for assessing risks from low-dose exposures, where only a small proportion of cells are directly hit. Bystander effects have been observed largely by using single-cell in vitro systems that do not have realistic multicellular morphology; no studies have as yet been reported in three-dimensional, normal human tissue. Given that the bystander phenomenon must involve cell-to-cell interactions, the relevance of such single-cell in vitro studies is questionable, and thus the significance of bystander responses for human health has remained unclear. Here, we describe bystander responses in a three-dimensional, normal human-tissue system. Endpoints were induction of micronucleated and apoptotic cells. A charged-particle microbeam was used, allowing irradiation of cells in defined locations in the tissue yet guaranteeing that no cells located more than a few micrometers away receive any radiation exposure. Unirradiated cells up to 1 mm distant from irradiated cells showed a significant enhancement in effect over background, with an average increase in effect of 1.7-fold for micronuclei and 2.8-fold for apoptosis. The surprisingly long range of bystander signals in human tissue suggests that bystander responses may be important in extrapolating radiation risk estimates from epidemiologically accessible doses down to very low doses where nonhit bystander cells will predominate.bystander ͉ normal human tissue ͉ radiological risk

Inducible response required for repair of low-dose radiation damage in human fibroblasts

“…First, it could be possible that the level of DSBs in the neighboring cells affects the efficiency of repair [i.e., a cell may not repair its break when the neighboring cells are devoid of any DSBs (which is the case after 10 mGy and below) but may show efficient repair if all cells of a population harbor a break (at 40-80 mGy and above)]. Such an explanation would require an intercellular communication or bystander mechanism, which has been reported for cells and tissues (35). However, to date, we have no solid evidence that a bystander-like mechanism underlies the inefficient repair at low doses.…”

Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

“…Several multicellular tissue models summarised in table 2, have been used to investigate RIBEs ex vivo using sections of porcine ureter (26,27) and reconstructed 3D skin models (28,29). Recently, Sheridan et al, (31) observed RIBEs manifest as elevated DNA damage in nonadjacent colon tissue obtained from patients receiving post neoadjuvant radiotherapy.…”

New challenges in radiobiology research with microbeams

“…Three-dimensional models can reproduce many of the tissue characteristics in vivo (Griffith and Swartz 2006) and are therefore ideal targets in microbeams for studying non-targeted effects. So far, mostly skin constructs have been used at microbeams (Belyakov et al 2005;Sedelnikova et al 2007;Schmid et al 2010;Miller et al 2011), but new organotypic slice culture methods offer the possibility of irradiating parts from all kinds of human tissues and to study their late response (Merz et al 2010). The tissue models at microbeams can be very useful to clarify the role of cell signaling and tissue remodeling in radiation response.…”