Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
Laboratory of RedOx Biology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
J Leukoc Biol. 2022 Mar;111(3):585-596. doi: 10.1002/JLB.3A0120-050RR. Epub 2021 May 27.
Evidence shows that tumor cells abundantly produce and release extracellular vesicles (EVs) that can interact with stromal cells and modulate their functions. In the tumor neighborhood, neutrophils can assume both antitumor and pro-tumor phenotypes, known as TAN-N1 and TAN-N2, respectively. Nevertheless, the contribution of tumor-derived EVs to the modulation of TAN phenotypes is still poorly understood. The effects of EVs produced by a metastatic human melanoma cell line (MV3) on the differentiation and functional changes in human neutrophils were investigated. Treatment with MV3-derived EVs induced neutrophil chemotaxis through a signaling pathway involving the CXCR2/PI3K-Akt axis, prolonged neutrophil life span, promoted formation of neutrophil extracellular traps with poor elastase activity, and increased reactive oxygen species production. In contrast, EVs also increased the expression of TAN-N2 molecular markers (such as ARG1, CXCR4, and VEGF) in neutrophils. They also impaired oxide nitric and peroxynitrite production and diminished cytotoxic activity against melanoma cells, inducing neutrophils into a pro-tumor profile. Remarkably, EV-stimulated neutrophils did not exhibit phagocytic activity. These data suggested that melanoma-derived EVs could activate neutrophils, allowing their migration toward the tumor microenvironment, and driving these cells to a pro-tumor/N2 polarization, thus contributing to tumor progression.
证据表明，肿瘤细胞大量产生和释放细胞外囊泡（EVs），可与基质细胞相互作用并调节其功能。在肿瘤微环境中，中性粒细胞可以呈现出抗肿瘤和促肿瘤表型，分别称为 TAN-N1 和 TAN-N2。然而，肿瘤来源的 EV 对 TAN 表型调节的贡献仍知之甚少。本研究旨在探讨转移性人黑色素瘤细胞系（MV3）产生的 EV 对人中性粒细胞分化和功能变化的影响。MV3 衍生的 EV 处理诱导中性粒细胞趋化，通过涉及 CXCR2/PI3K-Akt 轴的信号通路，延长中性粒细胞寿命，促进具有低弹性蛋白酶活性的中性粒细胞细胞外陷阱的形成，并增加活性氧物质的产生。相反，EVs 还增加了中性粒细胞中 TAN-N2 分子标志物（如 ARG1、CXCR4 和 VEGF）的表达。它们还损害了一氧化氮氧化物和过氧亚硝酸盐的产生，并降低了对黑色素瘤细胞的细胞毒性活性，诱导中性粒细胞向促肿瘤表型极化。值得注意的是，EV 刺激的中性粒细胞没有表现出吞噬活性。这些数据表明，黑色素瘤衍生的 EV 可以激活中性粒细胞，使其向肿瘤微环境迁移，并促使这些细胞向促肿瘤/N2 极化，从而促进肿瘤进展。
