Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients.
Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients.
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外泌体 PD-L1 和 N-钙粘蛋白预测骨肉瘤患者的肺转移进展
DOI：
10.1186/s12951-020-00710-6
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发表时间：
2020-10-22
影响因子：
10.2
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Wang J;Zhang H;Sun X;Wang X;Ren T;Huang Y;Zhang R;Zheng B;Guo W
背景近年来研究表明，来源于肿瘤的外泌体程序性死亡配体1（PD-L1）可诱导免疫抑制和肿瘤发病。然而，目前尚不清楚外泌体如何影响骨肉瘤（OS）的进展，以及PD-L1是否也存在于骨肉瘤患者的血清外泌体（Sr-外泌体）中。我们检测了70名OS患者、9名良性肿瘤患者和22名健康供体的血清外泌体。结果通过多种方法证实了OS患者血清和OS细胞系来源的外泌体的特征。我们发现OS患者与健康供体相比具有更高水平的外泌体PD-L1。同时，OS伴肺转移患者的外泌体PD-L1水平也高于无肺转移患者。其次，生物信息学分析表明，从OS患者中分离的Sr-外泌体可能参与OS患者的免疫功能和癌症发病机制的重要过程。Sr-外泌体差异表达的mRNA之间以PD-L1为中心的共表达网络表明外泌体N-cadherin与PD-L1表达密切相关。然后，我们证实了Sr-外泌体N-钙粘蛋白的水平较高的OS患者与肺转移相比，没有转移。此外，我们阐明了骨肉瘤来源的外泌体和外泌体-PD-L1在转移模型中促进肺转移。ROC（Receiver Operating Characteristic Curve）分析显示外泌体PD-L1、N-cadherin和N-cadherin/E-cadherin的AUC（Area Under Curve）分别为0.823、0.806和0.817，可区分有肺转移的OS患者和无肺转移的OS患者。OS患者血清中PD-L1和N-cadherin的检测可预测OS患者的肺转移进展。
BackgroundRecent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how exosomes influence osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. We examined serum exosomes from 70 OS patients, 9 patients with benign tumors and 22 healthy donors. OS-derived exosomes were functionally evaluated in vivo and in vitro.ResultsThe characteristics of exosomes derived from OS patient serum and OS cell lines were confirmed by several methods. We found OS patients had a higher level of exosomal PD-L1 compared to healthy donors. Meanwhile, OS patients with pulmonary metastasis also showed a relatively higher level of exosomal PD-L1 than patients without metastasis. Next, bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Co-expression network centered with PD-L1 among Sr-exosomal differently expressed mRNA demonstrated exosomal N-cadherin had a close relationship with exosomal PD-L1 expression. Then, we confirmed higher level of Sr-exosomal N-cadherin in OS patients with pulmonary metastasis compared to ones without metastasis. Furthermore, we elucidated osteosarcoma-derived exosomes and exosomal-PD-L1 promoted the pulmonary metastasis in metastatic models. ROC (Receiver Operating Characteristic Curve) analysis showed AUC (Area Under Curve) of 0.823 for exosomal PD-L1, 0.806 for exosomal N-cadherin and 0.817 for exosomal N-cadherin/E-cadherin to distinguish OS patients with pulmonary metastasis from ones without metastasis.ConclusionsOsteosarcoma stimulates pulmonary metastasis by releasing exosomes, that carry PD-L1 and N-cadherin. Detection of exosomal PD-L1 and N-cadherin from serum of OS patients may predict pulmonary metastasis progression for OS patients.
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