Department of Breast Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China.
Post-Doctoral Working Station, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China.
Aging (Albany NY). 2021 Mar 22;13(7):10415-10430. doi: 10.18632/aging.202802.
Exosome-mediated intercellular communication is considered to be an effective mode for malignant cells to transform biological behaviors in stromal cells. However, the mechanisms by which exosomes modulate macrophages within tumor microenvironment remain largely unclear. In this study, we found that both adriamycin-resistant breast cancer (BCa) cells and the corresponding exosomes (A/exo) were capable of inducing macrophages M2 polarization, which promoted the mobility, proliferation, migration and invasion of BCa cells. Since exosomes deliver microRNAs to affect cellular functions in recipient cells, we confirmed that miR-222 was significantly enriched in A/exo and could be successfully transferred to macrophages. Increased miR-222 level was also detected in exosomes derived from plasma and tissues of chemoresistant patients. Moreover, exosomal miR-222 from A/exo polarized M2 macrophages by targeting PTEN and activating Akt signaling pathway, which promoted BCa cells progression in a feed back loop. Co-culture of adriamycin-resistant BCa cells with macrophages in which miR-222 was upregulated or treated with A/exo facilitated tumor growth . Collectively, our data demonstrated that chemoresistant BCa cells could remodel macrophages within tumor microenvironment by secreting exosomal miR-222, which directly targeted PTEN and caused Akt cascade activation and macrophages M2 polarization. Our findings may provide a foundation for a promising strategy of BCa treatment by targeting exosomes or exosomal miR-222.
外泌体介导的细胞间通讯被认为是恶性细胞在基质细胞中转化生物学行为的有效方式。然而，外泌体调节肿瘤微环境中巨噬细胞的机制在很大程度上仍不清楚。在这项研究中，我们发现阿霉素耐药乳腺癌（BCa）细胞及其相应的外泌体（A/exo）均能够诱导巨噬细胞 M2 极化，从而促进 BCa 细胞的迁移、增殖、迁移和侵袭。由于外泌体将 microRNA 传递到受体细胞中以影响细胞功能，我们证实 miR-222 在 A/exo 中明显富集，并可成功转染至巨噬细胞。耐药患者血浆和组织来源的外泌体中也检测到 miR-222 水平增加。此外，A/exo 来源的外泌体 miR-222 通过靶向 PTEN 并激活 Akt 信号通路来极化 M2 巨噬细胞，从而在反馈环中促进 BCa 细胞的进展。阿霉素耐药 BCa 细胞与上调 miR-222 的巨噬细胞共培养或用 A/exo 处理可促进肿瘤生长。总之，我们的数据表明，耐药 BCa 细胞可通过分泌外泌体 miR-222 重塑肿瘤微环境中的巨噬细胞，该外泌体 miR-222 直接靶向 PTEN 并引起 Akt 级联激活和巨噬细胞 M2 极化。我们的研究结果可能为通过靶向外泌体或外泌体 miR-222 治疗 BCa 提供一个有前途的策略基础。
