Radiotherapy is one of the major cancer treatment strategies. Exposure to penetrating radiation causes cellular stress, directly or indirectly, due to the generation of reactive oxygen species, DNA damage, and subcellular organelle damage and autophagy. These radiation-induced damage responses cooperatively contribute to cancer cell death, but paradoxically, radiotherapy also causes the activation of damage-repair and survival signaling to alleviate radiation-induced cytotoxic effects in a small percentage of cancer cells, and these activations are responsible for tumor radio-resistance. The present study describes the molecular mechanisms responsible for radiation-induced cellular stress response and radioresistance, and the therapeutic approaches used to overcome radioresistance.

Epithelial–mesenchymal transition (EMT) causes epithelial cells to lose their polarity and adhesion property, and endows them with migratory and invasive properties to enable them to become mesenchymal stem cells. EMT occurs throughout embryonic development, during wound healing, and in various pathological processes, including tumor progression. Considerable research in the last few decades has revealed that EMT is invariably related to tumor aggressiveness and metastasis. Apart from the interactions between numerous intracellular signaling pathways known to regulate EMT, extracellular modulators in the tumor microenvironment also influence tumor cells to undergo EMT, with extracellular vesicles (EVs) receiving increasing attention as EMT inducers. EVs comprise exosomes and microvesicles that carry proteins, nucleic acids, lipids, and other small molecules to stimulate EMT in cells. Among EVs, exosomes have been investigated in many studies, and their role has been found to be significant with respect to regulating intercellular communications. In this review, we summarize recent studies on exosomes and their cargoes that induce cancer-associated EMT. Furthermore, we describe the possible applications of exosomes as promising therapeutic strategies.

Seong KM, et al. J Korean Med Sci. 2016 Feb;31(Suppl 1):S10-S23. http://dx.doi.org/10.3346/jkms.2016.31.S1.S10

People exposed to radiation in cancer therapy and nuclear accidents are at increased risk of cardiovascular outcomes in long‐term survivors. Extracellular vesicles (EVs) are involved in radiation‐induced endothelial dysfunction, but their role in the early stage of vascular inflammation after radiation exposure remains to be fully understood. Herein, we demonstrate that endothelial cell‐derived EVs containing miRNAs initiate monocyte activation in radiation‐induced vascular inflammation. In vitro co‐culture and in vivo experimental data showed that endothelial EVs can be sensitively increased by radiation exposure in a dose‐dependent manner, and stimulate monocytes releasing monocytic EVs and adhesion to endothelial cells together with an increase in the expression of genes encoding specific ligands for cell‐cell interaction. Small RNA sequencing and transfection using mimics and inhibitors explained that miR‐126‐5p and miR‐212‐3p enriched in endothelial EVs initiate vascular inflammation by monocyte activation after radiation exposure. Moreover, miR‐126‐5p could be detected in the circulating endothelial EVs of radiation‐induced atherosclerosis model mice, which was found to be tightly correlated with the atherogenic index of plasma. In summary, our study showed that miR‐126‐5p and miR‐212‐3p present in the endothelial EVs mediate the inflammatory signals to activate monocytes in radiation‐induced vascular injury. A better understanding of the circulating endothelial EVs content can promote their use as diagnostic and prognostic biomarkers for atherosclerosis after radiation exposure.

Curcumin, belonging to a class of natural phenol compounds, has been extensively studied due to its antioxidative, anticancer, anti-inflammatory, and antineurodegenerative effects. Recently, it has been shown to exert dual activities after irradiation, radioprotection, and radiosensitization. Here, we investigated the protective effect of curcumin against radiation damage usingD. melanogaster. Pretreatment with curcumin (100 μM) recovered the shortened lifespan caused by irradiation and increased eclosion rate. Flies subjected to high-dose irradiation showed a mutant phenotype of outstretched wings, whereas curcumin pretreatment reduced incidence of the mutant phenotype. Protein carbonylation and formation ofγH2Ax foci both increased following high-dose irradiation most likely due to generation of reactive oxygen species. Curcumin pretreatment reduced the amount of protein carbonylation as well as formation ofγH2Ax foci. Therefore, we suggest that curcumin acts as an oxidative stress reducer as well as an effective protective agent against radiation damage.

Breast cancer is a widely distributed type of cancer in women worldwide, and tumor relapse is the major cause of breast cancer death. In breast cancers, the acquisition of metastatic ability, which is responsible for tumor relapse and poor clinical outcomes, has been linked to the acquisition of the epithelial-mesenchymal transition (EMT) program and self-renewal traits (CSCs) via various signaling pathways. These phenomena confer resistance during current therapies, thus creating a major hurdle in radiotherapy/chemotherapy. The role of very low doses of radiation (LDR) in the context of EMT has not yet to be thoroughly explored. Here, we report that a 0.1 Gy radiation dose reduces cancer progression by deactivating the JAK1/STAT3 pathway. Furthermore, LDR exposure also reduces sphere formation and inhibits the self-renewal ability of breast cancer cells, resulting in an attenuated CD44⁺/CD24⁻ population. Additionally, in vivo findings support our data, providing evidence that LDR is a promising option for future treatment strategies to prevent cancer metastasis in breast cancer cases.