Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

Exosome-mediated miR-4655-3p contributes to UV radiation-induced bystander effects.

Radiation-induced bystander effects (RIBEs) refer to a series of reactions displaying in nonirradiated cells triggered by signals from irradiated cells. Though bystander effects induced by ionizing radiation have been well studied, there are still limited data on ultraviolet(UV) induced bystander effects(UV-RIBEs). Studies have verified that exosomes, acting as a new tool of intercellular communication, participate in ionizing radiation-induced bystander effect. The purpose of what we studied was to explore the function of exosomes in UV-RIBEs, and seeking the relevant mechanism. Human skin fibroblasts (HSFs) were exposed to a single dose of ultraviolet A (UVA) radiation (20 J/cm2) or ultraviolet B (UVB) radiation (60 mJ/cm2), respectively. Exosomes were isolated from the culture medium of HSFs by differential ultracentrifugation. Three endpoints relevant to potodamage were used in the evaluation of UV-RIBEs, which including the cell proliferation, oxidative damage, and apoptosis. Our results showed that exosomes from UV-irradiated cells contributed to UV-RIBEs. The expression of miR-4655-3p in exosomes increased after UV radiation and exosomes assisted in the transportation of miR-4655-3p between cells. The upregulation of miR-4655-3p enhanced the UV-RIBEs in the bystander cells. MiR-4655-3p restrained the expression of E2F2 through direct binding to its 3'-UTR. In addition, E2F2 contributed to the cell proliferation and decreased oxidative damage of HSFs. To sum up that exosomal miR-4655-3p plays a crucial role in UV-RIBEs and this function mentioned partially related to the inhibition of E2F2.

Exosomes Participate in the Radiotherapy Resistance of Cancers.

Radiotherapy is one of the main treatment modalities for cancer. However, some cancer patients will gradually develop resistance to radiotherapy, leading to tumor recurrence and metastasis. Radiation therapy usually promotes the secretion of exosomes from tumor cells and causes changes in their internal components. Accumulating evidence reveals that exosomes-mediated radiation-induced bystander effect (RIBE) is closely involved in radiotherapy resistance. In this article, we will discuss the relationship between exosomes and RIBE, highlight the effect of exosome components on resistance to radiation, and emphasize the role of exosome inclusion as a tumor biomarker for the prognosis of tumor treatment to develop new therapeutic approaches.

An emerging role of radiation­induced exosomes in hepatocellular carcinoma progression and radioresistance (Review).

The incidence rates of hepatocellular carcinoma (HCC) worldwide are increasing, and the role of radiotherapy is currently under discussion. Radioresistance is one of the most important challenges in the therapy of HCC compared with other local advanced, recurrent and metastatic cancers. The mechanisms of radioresistance are complex and remain to be fully understood; however, extracellular vesicles have been investigated in recent studies. Exosomes, which are 40­ to 150­nm extracellular vesicles released by cancer cells, contain multiple pathogenic components, including proteins, nucleic acids and lipids, and play critical functions in cancer progression. Emerging data indicate a diagnosis potential for exosomes in HCC, since radiation­derived exosomes promote radioresistance. Radiation­based therapy alters the contents and components of exosomes, suggesting that exosomes and their components may serve as prognostic and predictive biomarkers to monitor radiation response. Therefore, understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase our knowledge concerning the roles of exosomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment. The current review summarizes recent studies on exosome involvement in HCC and the molecular changes in exosome components during HCC progression. It also discusses the functions of exosomes in HCC therapy, and highlights the importance of exosomes in HCC progression and resistance for the development of novel therapies.

Identification of low-dose radiation-induced exosomal circ-METRN and miR-4709-3p/GRB14/PDGFRα pathway as a key regulatory mechanism in Glioblastoma progression and radioresistance: Functional validation and clinical theranostic significance.

Glioblastoma is a central nervous malignancy with a very poor prognosis. This study attempted to explore the role of exosomes induced by low-dose radiation-induced (ldrEXOs) and ldrEXOs-derived circ-METRN in glioblastoma progression and radioresistance at the molecular, cellular, animal, and clinical levels. Results in the present study revealed that low-dose radiation stimulated the secretion of ldrEXOs which delivered high levels of circ-METRN. And circ-METRN-abundant ldrEXOs increased the expression of γ-H2AX, indicating an efficient DNA damage-repair process in glioblastoma cells. The ldrEXOs-derived circ-METRN enhanced the glioblastoma progression and radioresistance via miR-4709-3p/GRB14/PDGFRα pathway. Up-regulating PDGFRα can rescue the tumor-promoting function of ldrEXOs in groups previously treated with inhibition of GRB14. Additionally, in-vivo experiments revealed that treatments with ldrEXOs promoted the growth of xenografted tumors and shortened the survival period. Furthermore, clinical researches indicated that circ-METRN may be transported into the bloodstream by exosomes in the early stages of fractionated radiotherapy. It has important clinical values to detect the serum exosomal circ-METRN in the early stage of radiotherapy, which is not only conducive to predict radioresistance and prognosis but also to assist MRI diagnosis in detecting the very early recurrence of glioblastoma. In summary, this study reveals for the first time that low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14/PDGFRα pathway, providing mechanistic insights into the roles of circRNAs and a valuable marker for therapeutic targets in glioblastoma.

An indispensable tool: Exosomes play a role in therapy for radiation damage.

Radiotherapy is one of the three main treatments for tumors. Almost 70% of tumor patients undergo radiotherapy at different periods. Although radiotherapy can enhance the local control rate of tumors and patients' quality of life, normal tissues often show radiation damage following radiotherapy. In recent years, several studies have shown that exosomes could be biomarkers for diseases and be involved in the treatment of radiation damage. Exosomes are nanoscale vesicles containing complex miRNAs and proteins. They can regulate the inflammatory response, enhance the regeneration effect of damaged tissue, and promote the repair of damaged tissues and cells, extending their survival time. In addition, their functions are achieved by paracrine signaling. In this review, we discuss the potential of exosomes as biomarkers and introduce the impact of exosomes on radiation damage in different organs and the hematopoietic system in detail.

Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species.

The precise mechanism of intercellular communication between cancer cells following radiation exposure is unclear. Exosomes are membrane­enclosed small vesicles comprising lipid bilayers and are mediators of intercellular communication that transport a variety of intracellular components, including microRNAs (miRNAs or miRs). The present study aimed to identify novel roles of exosomes released from irradiated cells to neighboring cancer cells. In order to confirm the presence of exosomes in the human pancreatic cancer cell line MIAPaCa­2, ultracentrifugation was performed followed by transmission electron microscopy and nanoparticle tracking analysis (NanoSight) using the exosome­specific surface markers CD9 and CD63. Subsequent endocytosis of exosomes was confirmed by fluorescent microscopy. Cell survival following irradiation and the addition of exosomes was evaluated by colony forming assay. Expression levels of miRNAs in exosomes were then quantified by microarray analysis, while protein expression levels of Cu/Zn­ and Mn­superoxide dismutase (SOD1 and 2, respectively) enzymes in MIAPaCa­2 cells were evaluated by western blotting. Results showed that the uptake of irradiated exosomes was significantly higher than that of non­irradiated exosomes. Notably, irradiated exosomes induced higher intracellular levels of reactive oxygen species (ROS) and a higher frequency of DNA damage in MIAPaCa­2 cells, as determined by fluorescent microscopy and immunocytochemistry, respectively. Moreover, six up­ and five downregulated miRNAs were identified in 5 and 8 Gy­irradiated cells using miRNA microarray analyses. Further analysis using miRNA mimics and reverse transcription­quantitative PCR identified miR­6823­5p as a potential candidate to inhibit SOD1, leading to increased intracellular ROS levels and DNA damage. To the best of our knowledge, the present study is the first to demonstrate that irradiated exosomes enhance the radiation effect via increasing intracellular ROS levels in cancer cells. This contributes to improved understanding of the bystander effect of neighboring cancer cells.

Characterization of exosome release and extracellular vesicle-associated miRNAs for human bronchial epithelial cells irradiated with high charge and energy ions.

Exosomes are extracellular vesicles that mediate transport of nucleic acids, proteins, and other molecules. Prior work has implicated exosomes in the transmission of radiation nontargeted effects. Here we investigate the ability of energetic heavy ions, representative of species found in galactic cosmic rays, to stimulate exosome release from human bronchial epithelial cells in vitro. Immortalized human bronchial epithelial cells (HBEC3-KT F25F) were irradiated with 1.0 Gy of high linear energy transfer (LET) 48Ti, 28Si, or 16O ions, or with 10 Gy of low-LET reference γ-rays, and extracellular vesicles were collected from conditioned media. Preparations were characterized by single particle tracking analysis, transmission electron microscopy, and immunoblotting for the exosomal marker, TSG101. Based on TSG101 levels, irradiation with high-LET ions, but not γ-rays, stimulated exosome release by about 4-fold, relative to mock-irradiated controls. The exosome-enriched vesicle preparations contained pro-inflammatory damage-associated molecular patterns, including HSP70 and calreticulin. Additionally, miRNA profiling was performed for vesicular RNAs using NanoString technology. The miRNA profile was skewed toward a small number of species that have previously been shown to be involved in cancer initiation and progression, including miR-1246, miR-1290, miR-23a, and miR-205. Additionally, a set of 24 miRNAs was defined as modestly over-represented in preparations from HZE ion-irradiated versus other cells. Gene set enrichment analysis based on the over-represented miRNAs showed highly significant association with nonsmall cell lung and other cancers.

Radiation Can Regulate the Expression of miRNAs Associated with Osteogenesis and Oxidation in Exosomes from Peripheral Blood Plasma.

OBJECTIVES: Radiotherapy is a common therapy in head and neck tumors, which may cause a side effect radiation bone injury (RBI). Furthermore, it has been investigated that microRNA (miRNA) expression levels were altered after radiotherapy. Exosomes play a role in bone formation as miRNA containers, while radiation affects exosomes composition, secretion, and function. So, our objective is to explore changes in miRNA levels during bone formation after radiotherapy and identify the differentially expressed miRNAs (DE-miRs) in plasma exosomes during the process of osteogenesis related to irradiation. MATERIALS AND METHODS: In this study, we analyzed nine samples from three rabbits exposed twice to radiation (15 Gy each) and detected DE-miRs from irradiated plasma exosomes during the process of osteogenesis by RNA sequencing. Further, we identified DE-miRs with significant differences and predicted their target genes via the bioinformatics analysis tools Targetscan v7.2 and miRPathDB v2.0. Finally, we identified radiation-responsive miRNAs and predicted their target genes during osteogenesis. RESULTS: Taken together, we have identified some DE-miRs in irradiated plasma exosomes, which were involved in several vital signaling pathways related to bone physiology, such as the Wnt pathway, MAPK cascade, and calcium modulating pathway. CONCLUSIONS: We have found that plasma exosomes are one of the ways by which radiation can affect bone metabolism and regeneration. However, the specific mechanisms of how these plasma exosomal miRNAs mediate the osteogenesis pathways must be further investigated. Clinical Relevance. Radiotherapy may cause radiation bone injury, and miRNA expression levels in rabbit plasma exosomes are altered after radiotherapy. High-throughput RNA sequencing can identify the differentially expressed miRNAs in irradiated plasma exosomes during the process of osteogenesis. These findings make sense to develop novel therapeutic strategies for treating radiation-induced bone injury disorders.

Exosomes and exosomal microRNA in non-targeted radiation bystander and abscopal effects in the central nervous system.

Localized cranial radiotherapy is a dominant treatment for brain cancers. After being subjected to radiation, the central nervous system (CNS) exhibits targeted effects as well as non-targeted radiation bystander effects (RIBE) and abscopal effects (RIAE). Radiation-induced targeted effects in the CNS include autophagy and various changes in tumor cells due to radiation sensitivity, which can be regulated by microRNAs. Non-targeted radiation effects are mainly induced by gap junctional communication between cells, exosomes containing microRNAs can be transduced by intracellular endocytosis to regulate RIBE and RIAE. In this review, we discuss the involvement of microRNAs in radiation-induced targeted effects, as well as exosomes and/or exosomal microRNAs in non-targeted radiation effects in the CNS. As a target pathway, we also discuss the Akt pathway which is regulated by microRNAs, exosomes, and/or exosomal microRNAs in radiation-induced targeted effects and RIBE in CNS tumor cells. As the CNS-derived exosomes can cross the blood-brain-barrier (BBB) into the bloodstream and be isolated from peripheral blood, exosomes and exosomal microRNAs can emerge as promising minimally invasive biomarkers and therapeutic targets for radiation-induced targeted and non-targeted effects in the CNS.

Phenotypic and Functional Characteristics of Exosomes Derived from Irradiated Mouse Organs and Their Role in the Mechanisms Driving Non-Targeted Effects.

Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators of NTE. Although exosome-mediated changes are well documented in radiation therapy and oncology, there is a lack of knowledge regarding the role of exosomes derived from inside and outside the radiation field in the early and delayed induction of NTE following IR. Therefore, here we investigated the changes in exosome profile and the role of exosomes as possible molecular signalling mediators of radiation damage. Exosomes derived from organs of whole body irradiated (WBI) or partial body irradiated (PBI) mice after 24 h and 15 days post-irradiation were transferred to recipient mouse embryonic fibroblast (MEF) cells and changes in cellular viability, DNA damage and calcium, reactive oxygen species and nitric oxide signalling were evaluated compared to that of MEF cells treated with exosomes derived from unirradiated mice. Taken together, our results show that whole and partial-body irradiation increases the number of exosomes, instigating changes in exosome-treated MEF cells, depending on the source organ and time after exposure.

Exosomes from adipose-derived stem cells attenuate UVB-induced apoptosis, ROS, and the Ca2+ level in HLEC cells.

Cartilage acid protein 1 (CRTAC1) encodes a protein containing the Ca2+binding domain, which can promote apoptosis of human lens epithelial cells (HLECs) induced by ultraviolet B radiation. Exosomes secreted from adipose-derived stem cells (ASC-exo) have been used to treat many diseases, but the effect of ASC-exo on cataracts has not been established. We hypothesized that ASC-exo has a therapeutic effect on cataracts by regulating CRTAC1. We established the UVB-induced injured HLECs model to test the interactions between CRTAC1 and miR-10a-5p, and the effect on the Ca2+ level and reactive oxygen species (ROS) generation in apoptotic HLECs. We found that UVB significantly increased the level of CRTAC1 expression and induced HLEC apoptosis, while ASC-exo inhibited the induction of UVB and exosome inhibitor reduced the inhibition of ASC-exo. The qRT-PCR results showed that miR-10a-5p had a low level of expression in cataract lesions, whereas CRTAC1 was highly expressed. There was a negative correlation between the expression of CRTAC1 and miR-10a-5p. ASC-exo reversed UVB-inhibited miR-10a-5p expression and miR-10a-5p negatively regulated CRTAC1. In vitro data showed that miR-10a-5p reversed UVB-induced ROS, apoptosis, and the Ca2+ level in HLECs. Overexpression of CRTAC1 reversed the induction of ASC-exo in UVB-injured HLECs, and low expression of CRTAC1 reversed the induction of miR-10a-5p inhibitor. By upregulating the level of miR-10a-5p expression and downregulating the level of CRTAC1 expression, exosomes from ASCs attenuated UVB-induced apoptosis, ROS generation, and the Ca2+ level in HLECs. Our research provides novel insight into the treatment methods and associated mechanisms underlying cataracts.

Exosome secreted by human gingival fibroblasts in radiation therapy inhibits osteogenic differentiation of bone mesenchymal stem cells by transferring miR-23a.

Radiation-induced fibrosis is recently established as a main reason for osteoradionecrosis of the jaw (ORNJ), anti-eradiation fibrosis drugs achieve satisfactory therapeutic effects. However, the molecular mechanism remain to be fully elucidated. In this study, we found the inhibitory effect of irradiation activated gingival fibroblasts on osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). Moreover, irradiation-activated-fibroblasts significantly increased miR­23a expression in hBMSCs. Decreased miR­23a enhanced osteogenic differentiation of BMSCs, and elevated miR­23a inhibited this process via directly targeting CXCL12. Finally, exosome released from irradiation-activated-fibroblasts inhibited osteogenic differentiation of BMSCs, and these exosome mediated delivery of miR-23a and further regulated miR-23a/CXCL12 axis in hBMSCs. Therefore, our findings suggest that by transferring miR-23a, exosome secreted by human gingival fibroblasts in radiation therapy serves a vital role in osteogenic differentiation of hBMSCs, which may provide novel clinical treatments for ORNJ.

Stellate Plasmonic Exosomes for Penetrative Targeting Tumor NIR-II Thermo-Radiotherapy.

Multifunctional gold (Au)-based nanomaterials with high atomic number (symbol Z) and strong absorbance in the second near-infrared window (NIR-II) property are emerging as promising candidates for tumor thermo-radiotherapy. The main limitations of applying Au-based nanomaterials to biomedical studies include the absence of active tumor-targeting ability, penetrating efficiency, and stability. In this study, we present a novel type of tumor cell-derived stellate plasmonic exosomes (TDSP-Exos) for penetrative targeted tumor NIR-II thermo-radiotherapy and photoacoustic imaging. The TDSP-Exos are abundantly and easily produced by the incubation of tumor cells with gold nanostars, based on which gold nanostars promote the exocytosis of exosomes from tumor cells. Compared with bare gold nanostars, the TDSP-Exos exhibit pronounced accumulation in deep tumor tissues and perform well in both PA imaging and NIR-II thermo-radiotherapy against the tumor. Moreover, the TDSP-Exos improve tumor hypoxia to enhanced radiotherapy by NIR-II photothermal therapy. This work indicates that the tumor cell-derived exosomes have the potential to function as a universal carrier of photothermal agents for targeted tumor NIR-II thermo-radiotherapy.

Effects of Hypoxia and Radiation-Induced Exosomes on Migration of Lung Cancer Cells and Angiogenesis of Umbilical Vein Endothelial Cells.

Numerous studies have shown that exosomes play important roles in tumor biology development. However, the function of exosomal protein in cancer progression under different oxygen condition after irradiation is poorly understood. In this study, non-small cell lung cancer (NSCLC) A549 cells were γ-ray irradiated under normoxic or hypoxic conditions, then the exosomes released from the irradiated cells were collected and co-cultured with nonirradiated A549 cells or human umbilical vein endothelial cells (HUVECs). It was found that the exosomes significantly promoted the proliferation, migration and invasion of A549 cells as well as the proliferation and angiogenesis of HUVECs. Moreover, the exosomes released from hypoxic cells and/or irradiated cells had more powerful driving force in tumor progression compared to that generated from normoxia cells. Meanwhile, the proteins contained in the exosomes derived from A549 cells under different conditions were detected using tandem mass tag (TMT), and their expression profiles were analyzed. It was found that the exosome-derived protein of angiopoietin-like 4 (ANGPTL4) contributed to the migration of A549 cells as well as the angiogenesis of HUVECs, suggesting its potential as an effective diagnostic biomarker of metastasis and even a therapeutic target of lung cancer.

MicroRNA Profile of Exosomes and Parental Cells is Differently Affected by Ionizing Radiation.

Exosomes are key mediators of cell-to-cell communication involved in different aspects of the response to ionizing radiation. The functional role of exosomes depends on their molecular cargo, including protein and miRNA content. In this work, we compared the miRNA profile of cells exposed to a high-dose of radiation and the exosomes released by those cells. FaDu cells (derived from human head and neck cancer) were exposed to 2 and 8 Gy doses, exosomes were purified from culture media at 36 h postirradiation using a combination of differential centrifugation, ultrafiltration and precipitation, then microRNA was analyzed using the RNA-seq approach. There were 439 miRNA species quantified, and significant differences in their relative abundance were observed between the cells and exosomes; several low-abundance miRNAs were over-represented while high-abundance miRNA were under-represented in exosomes. There were a few miRNA species markedly affected in irradiated cells and in exosomes released by these cells. However, markedly different radiation-induced effects were observed in both miRNA sets, which could be exemplified by miR-3168 significantly downregulated in cells and upregulated in exosomes. On the other hand, both 2 and 8 Gy radiation doses induced similar effects. Radiation-affected miRNA species present in exosomes are linked to genes involved in the DNA damage and cytokine-mediated response, which may suggest their hypothetical role in the exosome-mediated radiation-induced bystander effect reported elsewhere.

Premature senescence in human melanocytes after exposure to solar UVR: An exosome and UV-miRNA connection.

Ultraviolet radiation (UVR) can play two roles: induce cellular senescence and convert skin melanocytes into melanoma. To assess whether this conversion might rely on melanocytes having to first acquire a senescent phenotype, we studied the effects of physiological doses of UVR (UVA + UVB) on quiescent melanocytes in vitro. Repeated doses of UVR induced these melanocytes into a senescent-like state. Additionally, these cells secrete exosomes with specific miRNAs that differ in quantity from those of the un-irradiated melanocytes. Many of the exosomal miRNAs that were differentially enriched regulated genes comprising a "senescence core signature" and encoding factors of the senescence-messaging secretome (SASP), while a subset of the differentially reduced miRNAs targeted DNA repair genes that have been experimentally shown to be repressed in senescent melanocytes. Thus, the selection of specific miRNAs by exosomes and their release from melanocytes after exposure to UVR have activities in inducing these cells into premature senescence.

Exosomes carrying ALDOA and ALDH3A1 from irradiated lung cancer cells enhance migration and invasion of recipients by accelerating glycolysis.

Lung cancer has been recognized as the leading cause of cancer-related death worldwide. Despite the improvements of treatment, the distant metastasis and recurrence of lung cancer caused by therapy resistance is the biggest challenge in clinical management. Extracellular vesicles named exosomes play crucial roles in intercellular communication as signaling mediators and are involved in tumor development. In this study, we isolated exosomes from irradiated lung cancer cells and co-cultured the exosomes with other lung cancer cells. It was found that cellular growth and motility of recipient cells were facilitated. High-throughput LC-MS/MS assay of exosomal proteins and Gene Ontology enrichment analyses indicated that the metabolic enzymes ALDOA and ALDH3A1 had potential contribution in exosome-enhanced motility of recipient cells, and clinical survival analysis demonstrated the close correlations between ALDOA or ALDH3A1 expression and poor prognosis of lung cancer patients. After co-culturing with exosomes derived from irradiated cancer cells, the expressions of these metabolic enzymes were elevated and the glycolytic activity was promoted in recipient cancer cells. In conclusion, our data suggested that exosomes from irradiated lung cancer cells regulated the motility of recipient cells by accelerating glycolytic process, where exosomal ALDOA and ALDH3A1 proteins were important signaling factors.

Radiation-Induced Bystander Effect can be Transmitted Through Exosomes Using miRNAs as Effector Molecules.

The radiation-induced bystander effect (RIBE) is a destructive reaction in nonirradiated cells and is one primary factor in determining the efficacy and success of radiation therapy in the field of cancer treatment. Previously reported studies have shown that the RIBE can be mediated by exosomes that carry miRNA components within. Exosomes, which are one type of cell-derived vesicle, exist in different biological conditions and serve as an important additional pathway for signal exchange between cells. In addition, exosome-derived miRNAs are confirmed to play an important role in RIBE, activating the bystander effect and genomic instability after radiotherapy. After investigating the field of RIBE, it is important to understand the mechanisms and consequences of biological effects as well as the role of exosomes and exosomal miRNAs therein, from different sources and under different circumstances, respectively. More discoveries could help to establish early interventions against RIBE while improving the efficacy of radiotherapy. Meanwhile, measures that would alleviate or even inhibit RIBE to some extent may exist in the near future.

Tumor-derived extracellular vesicles: insights into bystander effects of exosomes after irradiation.

This review article aims to address the kinetic of TDEs in cancer cells pre- and post-radiotherapy. Radiotherapy is traditionally used for the treatment of multiple cancer types; however, there is growing evidence to show that radiotherapy exerts NTEs on cells near to the irradiated cells. In tumor mass, irradiated cells can affect non-irradiated cells in different ways. Of note, exosomes are nano-scaled cell particles releasing from tumor cells and play key roles in survival, metastasis, and immunosuppression of tumor cells. Recent evidence indicated that irradiation has the potential to affect the dynamic of different signaling pathways such as exosome biogenesis. Indeed, exosomes act as intercellular mediators in various cell communication through transmitting bio-molecules. Due to their critical roles in cancer biology, exosomes are at the center of attention. TDEs contain an exclusive molecular signature that they may serve as tumor biomarker in the diagnosis of different cancers. Interestingly, radiotherapy and IR could also contribute to altering the dynamic of exosome secretion. Most probably, the content of exosomes in irradiated cells is different compared to exosomes originated from the non-irradiated BCs. Irradiated cells release exosomes with exclusive content that mediate NTEs in BCs. Considering variation in cell type, IR doses, and radio-resistance or radio-sensitivity of different cancers, there is, however, contradictions in the feature and activity of irradiated exosomes on neighboring cells.