Tao Shi-Cong, Huang Ji-Yan, Wei Zhan-Ying, Li Zi-Xiang, Guo Shang-Chun
Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
Department of Stomatology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China.
Adv Biosyst. 2020 Sep;4(9):e2000152. doi: 10.1002/adbi.202000152. Epub 2020 Aug 16.
The prognosis for osteosarcoma (OS) continues to be unsatisfactory due to tumor recurrence as a result of metastasis and drug resistance. Several studies have shown that Ewing sarcoma associated transcript 1 (EWSAT1) plays an important role in the progression of OS. Exosomes (Exos) act as important carriers in intercellular communication and play an important role in the tumor microenvironment, especially in tumor-induced angiogenesis. Nonetheless, the specific mechanism via which EWSAT1 and Exos regulate OS progression is unknown, and whether they can be effective therapeutic targets also requires verification. Hence, in this study, it is aimed to investigate the mechanisms of action of EWSAT1 and Exos. EWSAT1 significantly promotes proliferation, migration, colony formation, and survival of OS. EWSAT1 regulates OS-induced angiogenesis via two mechanisms, called the "double stacking effect," which is a combination of the increase in sensitivity/reactivity of vascular endothelial cells triggered by Exos-carrying EWSAT1, and the EWSAT1-induced increase in angiogenic factor secretion. In vivo experiments further validates the "double stacking effect" and shows that EWSAT1-KD effectively inhibits tumor growth in OS. The above observations indicate that EWSAT1 can be used as not only a potential diagnostic and prognostic marker, but also as a precise therapeutic target for OS.
由于转移和耐药导致的肿瘤复发，骨肉瘤（OS）的预后仍然不尽人意。多项研究表明，尤因肉瘤相关转录本1（EWSAT1）在OS进展中起重要作用。外泌体（Exos）作为细胞间通讯的重要载体，在肿瘤微环境中发挥重要作用，尤其是在肿瘤诱导的血管生成中。然而，EWSAT1和Exos调节OS进展的具体机制尚不清楚，它们是否能成为有效的治疗靶点也需要验证。因此，本研究旨在探讨EWSAT1和Exos的作用机制。EWSAT1显著促进OS的增殖、迁移、集落形成和存活。EWSAT1通过两种机制调节OS诱导的血管生成，即“双重叠加效应”，它是由携带EWSAT1的Exos触发的血管内皮细胞敏感性/反应性增加与EWSAT1诱导的血管生成因子分泌增加的组合。体内实验进一步验证了“双重叠加效应”，并表明EWSAT1基因敲除有效地抑制了OS中的肿瘤生长。上述观察结果表明，EWSAT1不仅可以用作潜在的诊断和预后标志物，还可以作为OS的精确治疗靶点。
