Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
Department of Orthopedics, Jingzhou Central Hospital, Jingzhou, 434000, Hubei, China.
Eur J Pharmacol. 2021 May 15;899:174058. doi: 10.1016/j.ejphar.2021.174058. Epub 2021 Mar 21.
Although advances in osteosarcoma treatment have been made in recent decades, the survival rate for patients suffering from metastatic disease, especially lung metastasis, remains disappointing. Previous studies have confirmed that epithelial-to-mesenchymal transition (EMT) is associated with tumor metastasis, and several studies have suggested that osteosarcoma cells also exhibit EMT-like characteristics. In addition, Notch signaling is known to be related to the development and progression of human malignancies, including osteosarcoma. However, whether chemotherapy affects the EMT-like events and whether these events are medicated by Notch signaling remain to be elucidated. To address these issues, in the current work, osteosarcoma 143B cells were exposed to sublethal concentrations of the first-line chemotherapeutic agent cisplatin (DDP), which promoted cell migration, in vitro invasion, and in vivo lung metastasis. Furthermore, low concentrations of DDP upregulated mesenchymal phenotype-related genes and proteins and promoted EMT-like properties in osteosarcoma cells. In addition, low concentrations of DDP could activate the Notch receptor and its target genes. Finally, combined treatment of DDP with the Notch signaling pathway inhibitor DAPT, which can effectively downregulate mesenchymal phenotype-related genes and proteins, inhibited cell migration and invasion in vitro, and it decreased pulmonary metastatic nodules in vivo. The results of the current study supported the idea that low concentrations of DDP could induce EMT-like characteristics in osteosarcoma cells and could promote cell mobility in vitro, as well as pulmonary metastasis in vivo. Importantly, however, these biological processes are mediated by the Notch signaling pathway. Blocking the Notch signaling pathway can effectively attenuate the osteosarcoma EMT-like phenotype and its associated migration, invasion, and metastasis.
尽管在过去几十年中，骨肉瘤的治疗取得了进展，但患有转移性疾病（尤其是肺转移）的患者的生存率仍然令人失望。先前的研究已经证实，上皮-间充质转化（EMT）与肿瘤转移有关，并且有几项研究表明骨肉瘤细胞也表现出 EMT 样特征。此外， Notch 信号通路已知与人类恶性肿瘤的发生和进展有关，包括骨肉瘤。但是，化疗是否会影响 EMT 样事件，以及这些事件是否由 Notch 信号通路介导，仍有待阐明。为了解决这些问题，在目前的工作中，骨肉瘤 143B 细胞暴露于低浓度的一线化疗药物顺铂（DDP）中，这促进了细胞迁移、体外侵袭和体内肺转移。此外，低浓度的 DDP 上调了间充质表型相关基因和蛋白，并促进了骨肉瘤细胞的 EMT 样特性。此外，低浓度的 DDP 可以激活 Notch 受体及其靶基因。最后，DDP 与 Notch 信号通路抑制剂 DAPT 联合治疗可以有效下调间充质表型相关基因和蛋白，抑制细胞体外迁移和侵袭，并减少体内肺转移结节。本研究的结果支持低浓度 DDP 可诱导骨肉瘤细胞 EMT 样特征并促进细胞体外迁移以及体内肺转移的观点。然而，重要的是，这些生物学过程是由 Notch 信号通路介导的。阻断 Notch 信号通路可以有效减弱骨肉瘤 EMT 样表型及其相关的迁移、侵袭和转移。
