Background: Knowledge of radiobiology is of paramount importance to be able to grasp and
have an in-depth understanding of the consequences of ionizing radiation. One of the most important
effects of this physical stressor’s interaction to targeted and non-targeted cells, tissues and organs is on
the late effects on the development of primary and secondary cancers. Thus, an in-depth understanding
of the mechanisms of radiation carcinogenesis remains to be elucidated, and some studies have demonstrated
or proposed a role of non-targeted effect in excess risk of cancer incidence. The non-targeted
effect in radiobiology refers to a dynamic complex response in non-irradiated tissues caused by the release
of presumably of clastogenic factors from irradiated cells. Although, most of these responses in
non-targeted tissues have marked similarities to irradiated tissues, other studies have shown some differences.
Also, the non-targeted effect has shown sex and tissue specificity that are seen in irradiated
tissues too. So far, several studies have been conducted to depict mechanisms that may be involved in
this phenomenon. Epigenetic dysfunctions, DNA damage and cell death are responsible for initiation of
several signaling pathways that finally result in secretion of clastogenic factors. Moreover, studies have
shown that damage to both nucleus and mitochondrial DNA, membrane and some organelles is involved.
Oxidized DNA associated with other cell death factors stimulates secretion of inflammatory as
well as some anti-inflammatory cytokines from irradiated area. Additionally, oxidative stress that results
in damage to cellular structures to include cell membranes can affect secretion of exosomes and miRNAs.
These bystander effect exogenous mediators migrate to distant tissues and stimulate various signaling
pathways which can lead to changes in immune responses, epigenetic modulations and radiation
Conclusion: In this review, we focus on descriptive and hierarchical events with emphasis on the molecular
and functional interactions of ionizing radiation with cells to the mechanisms involved in cancer
induction in non-targeted tissues.
Keywords: Radiation, radiation carcinogenesis, radiotherapy, systemic effect, bystander effect, non-targeted effect, epigenetics,
DNA damage, clastogenic factors, cell cycle.
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