title: Systemic mechanisms and effects of ionizing radiation: A new 'old' paradigm of how the bystanders and distant can become the players.
abstract: Exposure of cells to any form of ionizing radiation (IR) is expected to induce a variety of DNA lesions, including double strand breaks (DSBs), single strand breaks (SSBs) and oxidized bases, as well as loss of bases, i.e., abasic sites. The damaging potential of IR is primarily related to the generation of electrons, which through their interaction with water produce free radicals. In their turn, free radicals attack DNA, proteins and lipids. Damage is induced also through direct deposition of energy. These types of IR interactions with biological materials are collectively called 'targeted effects', since they refer only to the irradiated cells. Earlier and sometimes 'anecdotal' findings were pointing to the possibility of IR actions unrelated to the irradiated cells or area, i.e., a type of systemic response with unknown mechanistic basis. Over the last years, significant experimental evidence has accumulated, showing a variety of radiation effects for 'out-of-field' areas (non-targeted effects-NTE). The NTE involve the release of chemical and biological mediators from the 'in-field' area and thus the communication of the radiation insult via the so called 'danger' signals. The NTE can be separated in two major groups: bystander and distant (systemic). In this review, we have collected a detailed list of proteins implicated in either bystander or systemic effects, including the clinically relevant abscopal phenomenon, using improved text-mining and bioinformatics tools from the literature. We have identified which of these genes belong to the DNA damage response and repair pathway (DDR/R) and made protein-protein interaction (PPi) networks. Our analysis supports that the apoptosis, TLR-like and NOD-like receptor signaling pathways are the main pathways participating in NTE. Based on this analysis, we formulate a biophysical hypothesis for the regulation of NTE, based on DNA damage and apoptosis gradients between the irradiation point and various distances corresponding to bystander (5mm) or distant effects (5cm). Last but not least, in order to provide a more realistic support for our model, we calculate the expected DSB and non-DSB clusters along the central axis of a representative 200.6MeV pencil beam calculated using Monte Carlo DNA damage simulation software (MCDS) based on the actual beam energy-to-depth curves used in therapy.
authors.affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece.
authors.forename: Zacharenia
authors.initials: Z
authors.lastname: Nikitaki
authors.affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece.
authors.forename: Ifigeneia V
authors.initials: IV
authors.lastname: Mavragani
authors.affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece.
authors.forename: Danae A
authors.initials: DA
authors.lastname: Laskaratou
authors.affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece.
authors.forename: Violeta
authors.initials: V
authors.lastname: Gika
authors.affiliation: Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Vadim P
authors.initials: VP
authors.lastname: Moskvin
authors.affiliation: InSyBio Ltd, 109 Uxbridge Road, W5 5TL London, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Theofilatos
authors.affiliation: Proteomics Research Unit, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Vougas
authors.affiliation: Department of Radiation Oncology, University of Washington School of Medicine, School of Medicine, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stewart
authors.affiliation: Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece. Electronic address: alexg@mail.ntua.gr.
authors.forename: Alexandros G
authors.initials: AG
authors.lastname: Georgakilas
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000528:radiation effects*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D042822:Genomic Instability; D006801:Humans; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing
chemical_list: D011506:Proteins
keywords: Bioinformatics; Bystander effects; Ionizing radiation; Monte Carlo DNA damage simulation; Non-targeted effects; Proton therapy; Systemic effects