**4. Exosome in radio-resistance**

Radio-resistance is induced by certain conditions or pathways, and eventually limits the efficacies of radiation therapy. Molecular oxygen status is recognized as one of the most influential factors regulating radio-resistance. In general, cancer cells may be radio-resistant under hypoxic conditions in solid tumors [63–65]. Adapting to the hypoxic conditions, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. It is widely known that tumor cells in the hypoxia microenvironment induced radio-resistance by hypoxia-inducible factor 1 (HIF-1) and several pathways such as phosphatidylinositol 3-kinase Akt/mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB) [66–68]. Tumor-derived exosomes promote angiogenesis by suppressing the expression of factor-inhibiting hypoxia-inducible factor 1 (HIF-1) and by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. The hypoxic condition induces angiogenesis. Uptake of the tumor-derived exosomes by normal endothelial cells activates angiogenic signaling pathways in endothelial cells and stimulates new vessel formation [69]. Exosomes can affect T cells through direct receptor-ligand interactions, but in ECs, exosomes usually use the internalization pathway [70].

The NF-κB is known as the most important transcription factors regulating the expression of a large number of genes involved in cellular processes, such as inflammatory responses, cellular growth, developmental processes and apoptosis. The inducers of NF-κB activity are highly variable, including ROS, TNFα, IL-1β, LPS, isoproterenol, ionizing radiation, viruses, and chemotherapeutic reagents [71]. Active NF-κB enters the nucleus and up-regulates the transcription of Bcl-2, Bcl-xL, XIAP, survivin and Akt leading to chemo- and radio-resistance. Yoshida and coworkers demonstrated that NF-κB is the strongest indicator of radio-resistance in laryngeal squamous cell carcinoma cases treated with radiation therapy alone without surgery nor combined chemotherapy [72]. As for the relationship between exosomes and NF-κB, Zeng et al. elaborated that exosomal miR-183-5p shuttled by M2-TAM mediated Akt/NF-κB pathway to accelerate colon cancer progression through targeting thioesterase superfamily member 4 (THEM4) [73]. Li J et al. demonstrated that hypoxic colorectal cancer-derived extracellular vesicles deliver microRNA-361-3p to facilitate cell proliferation by targeting TRAF3 via the noncanonical NF-κB pathways [74]**.**

Farias et al. reported that exosomes derived from irradiated MSCs (mesenchymal stem cells) delay tumor growth and reduce metastasis after treatment with MSCplusradiation therapy [75]. In this report, the authors indicate that the effect of MSCs on the tumor is associated with ANXA1; recognized as an anti-inflammatory mediator which regulates migration and cellular responses. They also showed MSCs plus radiation therapy administered on an experimental murine model had a positive effect on the tumor-volume reduction of the contralateral, untreated tumor [75]. According to these reports, exosomes derived from MSC are expected to be able to improve the efficacy of irradiation for radiation-resistant cancers.
