PDF(Pubmed)
Abstract：
Osteosarcoma, a prevalent primary malignant bone tumor, often presents with lung metastases, severely impacting patient survival rates. Extracellular vesicles, particularly exosomes, play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions. However, the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure, with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown. This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site. This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate (MARCKS) expression. Addressing this phenomenon, in this study we employ cationic bovine serum albumin (CBSA) to form nanoparticles (CBSA-anta-194/215) via electrostatic interaction with antagomir-miR-194/215. These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles (anta-194/215@Exo) targeting osteosarcoma lung metastatic sites. Intervention with bioengineered exosome mimetics (anta-194/215@Exo) not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice. These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS, making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.
摘要：
骨肉瘤,一种常见的原发性恶性骨肿瘤，常伴有肺转移，严重影响患者生存率。细胞外囊泡，特别是外泌体，在骨肉瘤相关肺部病变的形成和进展中起关键作用。然而,原发性骨肉瘤和外泌体介导的肺部病变之间的联系仍然模糊，肺转移灶对骨肉瘤进展的潜在影响尚不清楚。这项研究揭示了一种创新机制，通过该机制，源自骨肉瘤肺转移部位的外泌体将miR-194/215簇运输到原发肿瘤部位。这种运输通过下调肉豆蔻酰化的富含丙氨酸的C激酶底物（MARCKS）表达来增强肺转移能力。解决这一现象，在这项研究中,我们使用阳离子牛血清白蛋白(CBSA)通过与antagomir-miR-194/215的静电相互作用形成纳米颗粒(CBSA-anta-194/215).将这些纳米颗粒加载到靶向骨肉瘤肺转移部位的核酸耗尽的外泌体膜囊泡(anta-194/215@Exo)中。生物工程外泌体模拟物（anta-194/215@Exo）的干预不仅会阻碍骨肉瘤的进展，而且还会显着延长荷瘤小鼠的寿命。这些结果表明，肺转移灶来源的外泌体通过转移miR-194/215簇靶向MARCKS启动原发性骨肉瘤肺转移，使miR-194/215簇成为抑制骨肉瘤肺转移患者进展的有希望的治疗靶标。
