Mediation of radiation-induced bystander effect and epigenetic modification: The role of exosomes in cancer radioresistance

Abstract

Exosomes are nano-sized extracellular vesicles produced by almost all mammalian cells. They play an important role in cell-to-cell communication by transferring biologically active molecules from the cell of origin to the recipient cells. Ionizing radiation influences exosome production and molecular cargo loading. In cancer management, ionizing radiation is a form of treatment that exerts its cancer cytotoxicity by induction of DNA damage and other alterations to the targeted tissue cells. However, normal bystander non-targeted cells may exhibit the effects of ionizing radiation, a phenomenon called radiation-induced bystander effect (RIBE). The mutual communication between the two groups of cells (targeted and non-targeted) via radiation-influenced exosomes enables the exchange of radiosensitive molecules. This facilitates indirect radiation exposure, leading, among other effects, to epigenetic remodeling and subsequent adaptation to radiation. This review discusses the role exosomes play in epigenetically induced radiotherapy resistance through the mediation of RIBE.

Keywords: Epigenetic changes; Exosomes; Ionizing radiation; Radiation-induced bystander effect; Radiotherapy resistance.

Fig. 1

Schematic illustration of exosome biogenesis and release. Exosomes are derived from the endocytic invagination of the plasma membrane, leading to the formation of multivesicular endosomes (MVEs). These MVEs serve as the source from which exosomes are generated and subsequently released into the extracellular space through exocytosis. Following their uptake via endocytosis or receptor-mediated mechanisms, exosomes are assimilated by recipient cells in either a paracrine or an autocrine manner. Within these cells, they play a potential role in stimulating various signaling pathways.

Fig. 2

Schematic illustration of radiation-induced exosome biogenesis and release. While canonical exosome release is typically regulated by the Golgi apparatus, radiation exposure triggers exosome formation and release by activating the p53-DNA-dependent damage-transcription factor. As radiation damages DNA, it activates p53-DNA damage transcription factor and further stimulates transmembrane protein tumor suppressor-activated Pathway 6 (TSAP6) whose expression influences exosome release.

Fig. 3

Exosomes may induce radiation resistance through the mediation of radiation-induced bystander effect and epigenetic remodeling. Radiation exposure (1) induces DNA damage-mediated cell death or DNA damage repair or misrepair which further induces genomic instability (2). Radiation induces exosome biogenesis and release (3). Cargo-dysregulated exosomes are taken up by the recipient cell (4) where they induce genomic instability and epigenetic remodeling (5). Recipient cells produce exosomes loaded with radio-adaptive molecules (6) and are released into TME. Released exosomes are taken up by other recipient cells, to which radiation resistance is induced (7).