Sun Yu, Xiao Wenjun, Yu Yang, Jiang Yuchen, Xiao Zhijie, Huang Defa, Zhong Tianyu, Li Jiang, Xiang Xi, He Yulong, Li Zhigang
Guangdong Provincial Key Laboratory of Digestive Cancer Research; Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China; Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Exp Cell Res. 2023 May 15;426(2):113565. doi: 10.1016/j.yexcr.2023.113565. Epub 2023 Mar 22.
In recent years, we have realized that extracellular vesicles (EVs) play a critical role in regulating the intercellular communication between tumor and immune cells in the tumor microenvironment (TME). Tumor-derived extracellular vesicles (TDEVs) profoundly affect the functional changes of tumor-associated macrophages (TAMs) and promote their M2 polarization. Meanwhile, macrophages have a strong phagocytic ability in phagocytosing apoptotic cells. Especially in the course of chemotherapy or radiotherapy, TAMs can phagocytose and remove apoptotic tumor cells, showing anti-inflammatory and pro-tumor effects. However, the underlying mechanisms by which TDEVs regulate macrophage phagocytosis of apoptotic tumor cells have not been fully elucidated. In this study, we focused on the effect of colorectal cancer-derived extracellular vesicles (CRC-EVs) on macrophages. We demonstrated that CRC-EVs enhanced macrophage phagocytosis of apoptotic CRC cells. We then determined that heat shock protein 70 (HSP70) carried in CRC-EVs was responsible for this effect by using mass spectrometry-based proteomic analysis and the CRISPR-Cas9 system. Through transcriptome sequencing of macrophages, we found that the enhanced phagocytosis of macrophages was mainly due to the up-regulation of the macrophage receptor with collagenous structure (MARCO). In addition, we confirmed that the up-regulation of MARCO was mediated by the AKT-STAT3 signaling pathway. Taken together, this study revealed a novel EVs-mediated macrophage phagocytosis mechanism involved in the clearance of apoptotic tumor cells in the TME. Targeting TDEVs may have potential therapeutic applications in tumor treatment.
近年来，我们已经认识到细胞外囊泡（EVs）在调节肿瘤微环境（TME）中肿瘤细胞与免疫细胞之间的细胞间通讯方面发挥着关键作用。肿瘤来源的细胞外囊泡（TDEVs）深刻影响肿瘤相关巨噬细胞（TAMs）的功能变化并促进其M2极化。同时，巨噬细胞在吞噬凋亡细胞方面具有很强的吞噬能力。特别是在化疗或放疗过程中，TAMs可以吞噬并清除凋亡的肿瘤细胞，表现出抗炎和促肿瘤作用。然而，TDEVs调节巨噬细胞吞噬凋亡肿瘤细胞的潜在机制尚未完全阐明。在本研究中，我们聚焦于结直肠癌来源的细胞外囊泡（CRC-EVs）对巨噬细胞的影响。我们证明CRC-EVs增强了巨噬细胞对凋亡CRC细胞的吞噬作用。然后，我们通过基于质谱的蛋白质组学分析和CRISPR-Cas9系统确定，CRC-EVs中携带的热休克蛋白70（HSP70）是造成这种效应的原因。通过对巨噬细胞的转录组测序，我们发现巨噬细胞吞噬作用增强主要是由于具有胶原结构的巨噬细胞受体（MARCO）上调所致。此外，我们证实MARCO的上调是由AKT-STAT3信号通路介导的。综上所述，本研究揭示了一种新的EVs介导的巨噬细胞吞噬机制，该机制参与TME中凋亡肿瘤细胞的清除。靶向TDEVs可能在肿瘤治疗中具有潜在的治疗应用价值。
