Non-targeted effects of radiation: a personal perspective on the role of exosomes in an evolving paradigm

Figures & data

Table 1. General definitions of non-targeted effects (NTE) of radiation.

NTE	Definition
NTE NTE of ionizing radiation NNNNNNTENNNNN	NTE are defined as responses that are expressed in the absence of direct ionizing radiation deposition in nuclear DNA. The majority of NTE are low dose effects and usually display non-linear dose-response relationships. NTE do not contradict “target theory” but contribute to a concept of an “expanding target” which is linked to underlying biological signaling triggered by physical dose deposition (Kadhim et al. 2013; Bright and Kadhim 2018)
Radiation induced genomic instability (RIGI)	RIGI is defined as a temporary or long-term increase in the rate of genetic changes in the genome of irradiated cells over many cell generations (Limoli 2017))
Radiation induced bystander effects (RIBE)	RIBE are radiation induced effects observed in un-irradiated cells that are in close proximity to irradiated cells as a result of communication with irradiated cells; either by secretion of soluble substances or signaling via gap junctions (Mothersill et al. 2018)
Abscopal effects (AE)	AE are transmitted between irradiated and un-irradiated tissues outside of the irradiated volume via systemic signaling (Pouget et al. 2018)
Adaptive response (AR)	AR is characterized by biological systems which are exposed to a small “priming” radiation dose to attenuate the effects of a larger challenging dose through activation of numerous signaling pathways (Calabrese and Baldwin 2001)

Figure 1. Exposure to ionizing radiation can cause DNA damage to nuclear DNA. The cell can either repair any damage presents (blue cells) or mis-repair the damage fixing an aberration that is present in the progeny of that cell (pink cells). Alternatively, an ongoing process may occur in which new aberrations appear in some cells at a delayed time point.

Figure 2. Exposure to irradiation can induce intercellular signaling with the appearance of radiation-like effects in un-irradiated cells. A number of factors such as reactive oxygen/nitrogen (ROS/RNS), cell free DNA (cfDNA) species, TNF-related apoptosis-inducing ligand (TRAIL) as well as a host of other proteins (various black shapes) have been proposed.

Figure 3. Link between bystander effect and genomic instability.

Table 2. Extracellular vesicle (EV) definitions in the literatures.

Name	Definition	Reference
Microvesicles	Microvesicles are extracellular vesicles that are released from the cell membrane. In multicellular organisms, microvesicles and other EVs vary in size and are found both in tissues and in many types of body fluids	Ratajczak and Ratajczak (2020)
Apoptotic bodies	Apoptotic bodies range in size from 500 to 2000 nm in diameter and are made up of cytoplasm and tightly packed organelles. They are generated as a result of “budding”, a process which consist of extensive plasma membrane blebbing followed by karyorrhexis and disassociation of cell fragments	Elmore (2007) and Stolzing and Grune (2004)
Ectosomes	Ectosomes are shedding membrane vesicles that bud directly from cell membranes of neutrophils or monocytes. They are variable in size from 100 to 1000 nm in diameter, while it is debatable that vesicles larger than 350–400 nm are true ectosomes	Sadallah et al. (2011) and Melodies (2016)
Oncosomes	They are membrane-derived micro and nano scale extracellular vesicles that are released by cancer cells and carry oncogenic messages and protein complexes across cell borders	Meehan et al. (2016)
Exosomes	Exosomes comprise homogenous population of membrane vesicles that range in size between 40 and 100 nm in diameter. They are derived from the endocytic recycling pathway. In endocytosis, endocytic vesicles form at the plasma membrane and fuze to form early endosomes, which then mature into late endosomes where intraluminal vesicles bud off into an intra-cytoplasmic lumen. These multivesicular bodies directly fuze with the plasma membrane and release exosomes into the extracellular space rather than fuzing with lysosome. Instead of fuzing with the lysosome, these multivesicular bodies directly fuze with the plasma membrane and release exosomes into the extracellular space. Exosomal markers used for identification of these vesicles include CD63, CD9 and TSG101	Pant et al. (2012), Mayers and Audhya (2012), Mathivanan et al. (2012) and Record et al. (2011)

Figure 4. Exosome biogenesis, secretion, and cell communication via exosomes.

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