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  • Besides its association with tumor angiogenesis EBER


    Besides its association with tumor angiogenesis, EBER-mediated VCAM-1 expression might contribute to tumor progression in various ways. The last few years have witnessed an ever-increasing body of knowledge on the molecular understanding of tumorigenicity and metastasis, and an impressive variety of VCAM-1 functionalities in cancer have been elucidated. Endothelial VCAM-1 has been found to mediate tumor cell adhesion, transendothelial migration, and myeloid cell adhesion, all of which collectively predispose tissues to tumor metastasis [36]. EBV is closely related to NPC metastasis, however, previous research has concentrated on understanding this association by focusing on mechanisms of EBV-encoded proteins and RNAs within tumor cells. Furthermore, although recent in vitro evidence suggests that NPC ABT-263 (Navitoclax) can communicate with endothelial cells via exosomes [23], the impact of exosome-derived EBERs on endothelial cells located in NPC parenchymal tissues and the underlying molecular mechanisms are not fully understood. Our present research demonstrated the association between EBERs and VCAM-1 via TLR3/RIG-I-mediated transcription activation, illustrating the impact of NPC EV-derived EBERs on tumor angiogenesis. EBER-stimulated VCAM-1 per se was verified to be angiogenic in the present study, and the stimulation of VCAM-1 might further directly contribute to metastasis by promoting tumor cell adhesion, transendothelial migration, and myeloid cell recruitment and adhesion, which affect primary tumor metastasis [45,46]. Hence, the causal relationship between EBERs and VCAM-1 may be vital for NPC metastasis, which should be the focus of further study. EBV is a γ-herpesvirus that has been a leading candidate implicated in triggering several autoimmune diseases and cancer. Apart from its capability to infect epithelial cells and lymphocytes, it can infect endothelial cells or fibroblasts in vitro [31,47,48]. This seems to contradict our results by raising the possibility of EBV infection rather than EVs accounting for the presence of EBERs in endothelial cells in NPC parenchymal tissues. We propose the following explanations in support of our results. First, IHC staining indicated that EBV-encoded LMP1 never appeared in the epithelial cells of NPC tissues, in contrast to the detection of LMP1 in EBV-infected fibroblasts in systemic sclerosis [48]. Second, most of the published reports investigated the infection of endothelial cells by EBV with in vitro models and did not validate their hypothesis with clinical samples [47,49]. Third, EBERs positive endothelial cells were only evident in the vicinity of some EBERs intensively stained NPC cells, while there were no presence of EBERs in most endothelial cells in EBV positive NPC parenchymal tissues. Finally, despite the possibilities of EBV infection, EVs derived from EBV positive NPC cells are capable of delivering exosomes to co-cultured endothelial cells [23,50], which is reminiscent of our observation that EVs-derived EBERs were proven to be angiogenic. The following are the supplementary data related to this article.
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    Introduction Osteosarcoma (OS), which is derived from primitive bone-forming mesenchymal cells, is ranked as the most common primary bone malignancy in children and adolescents worldwide [1]. It has been reported that the incidence of OS is 0.2–3/100,000 in children and 0.8–11/100,000 in adolescents [2]. Currently, surgical resection and neoadjuvant chemotherapy constitute the major treatment regimens for OS. However, with the advancement of surgical techniques and the application of various novel effective chemotherapy drugs, the 5-year survival rate of OS patients has been improved to 60–70% [[3], [4], [5]]. Unfortunately, the overall survival rate is still not optimistic, mainly because of tumor recurrence and drug resistance in recent decades. Therefore, the development of new drugs and treatment approaches is an urgent matter to improve therapeutic outcomes in OS patients.