Intercellular Communication in Response to Radiation Induced Stress: Bystander Effects in Vitro and in Vivo and Their Possible Clinical Implications

Communication between cells is important for maintaining homeostasis, the physiological regulatory processes that keep the internal environment of a system in a constant state. A disease can disturb the internal equilibrium of cells, and this can be further disrupted by various therapies. Malignances are the diseases that need to be treated by highly aggressive methods, such as radiotherapy, which affects not only tumor cells but also normal cells adjacent to the tumor and usually included in the radiation field. This treatment may interfere with normal intercellular communication. It has been a central radiobiological dogma for decades that damaging effects of ionizing radiation are the result of direct ionization of cell structures, particularly DNA, or are due to indirect damage via water radiolysis products. Indeed, DNA damage such as chromosomal aberrations, micronuclei, sister chromatid exchange and mutagenesis result from ionizing radiation. All of these types of damage, if unrepaired, can lead to cell death or, if misrepaired, can lead to genomic instability and carcinogenesis. Recently however, the attention was focused on the third mechanism, a phenomenon termed “radiation induced bystander effect” (RIBE). This phenomenon is a non-targeted effect where molecular signal(s) produced by directly irradiated cells elicit subsequent responses in unirradiated neighbors. These responses are manifested as decreased survival, increased sister chromatid exchanges (SCE), chromosomal aberrations (CA), micronucleus (MN) formation, gene mutations, apoptosis, genomic instability, neoplastic transformation and a variety of damage-inducible stress responses (reviewed in Morthersill and Seymour, 2001, Lorimore et al., 2003, Morgan, 2003a, 2003b, Little, 2006a,b, Chapman et al. 2008, Rzeszowska-Wolny et al., 2009a). Bystander effect accompanies very low doses of alpha particles (mGy and cGy), (Nagasawa and Little, 1992, Lorimore et al., 1998), as well as irradiation of cells with a low LET radiation (Xand gamma rays), even at conventionally used higher clinical doses (Morthersill and Seymour, 1997, 1998, 2002b, Przybyszewski et al., 2004). The mechanisms responsible for RIBE are complex and not quite well-known. Mechanisms by which bystander signals may be transmitted from irradiated to non-irradiated cells involve direct cell-to-cell contact mediated by gap