Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Mol Ther. 2018 Feb 7;26(2):568-581. doi: 10.1016/j.ymthe.2017.11.016. Epub 2017 Nov 29.
Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.
缺氧是癌症中最常见的特征，它与免疫抑制微环境的建立有关。最近的研究表明，细胞外囊泡（EV）介导的癌症-基质相互作用被认为在调节各种细胞生物学功能方面发挥着关键作用，对受体细胞具有表型后果。然而，EV 和癌症进展过程中缺氧之间的关系的机制在很大程度上仍然未知。在这项研究中，我们发现来自缺氧肺癌的 EV 通过 miR-103a 的转移增加了 M2 型极化。缺氧癌细胞衍生的 EV miR-103a 引起的 PTEN 水平降低增加了 AKT 和 STAT3 的激活以及几种免疫抑制和促血管生成因子的表达。相比之下，miRNA 抑制剂抑制 miR-103a 可有效降低缺氧诱导的癌症介导的 M2 型极化，从而改善肿瘤浸润巨噬细胞的细胞因子增殖。巨噬细胞接受癌细胞衍生的 EV miR-103a 的反馈，进一步增强癌症进展和肿瘤血管生成。最后，肺癌患者的循环 EV miR-103a 水平升高，并与 M2 极化密切相关。总之，我们的研究结果描绘了一种新的机制，即肺癌细胞通过 EV 诱导免疫抑制和促肿瘤巨噬细胞，并激发进一步研究 EV 抑制或 PTEN 恢复在免疫治疗中的临床应用。
