Laboratório de Biologia RedOx, Universidade Federal do Rio de Janeiro, Rio de Janeiro 60440-593, Brazil.
Laboratório de Farmacologia Celular e Molecular, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 23968-000, Brazil.
Cells. 2022 Jun 9;11(12):1875. doi: 10.3390/cells11121875.
Immune system cells, including neutrophils, are recruited by the tumor microenvironment as a site of chronic inflammation and begin to favor tumor growth. Neutrophils present in the tumor site are called tumor-associated neutrophils (TAN) and can present two phenotypes: N1 (antitumor) or N2 (pro-tumor). Evidence shows the high capacity of immune system cells to interact with extracellular vesicles (Evs) released by tumor cells. Evs can modulate the phenotype of cells within the immune system, contributing to tumor development. Here, we investigated the role of MDA-MB-231-derived Evs upon the polarization of neutrophils towards an N2 phenotype and the underlying mechanisms. We observed that neutrophils treated with Evs released by MDA cells (MDA-Evs) had their half-life increased, increased their chemotactic capacity, and released higher levels of NETs and ROS than neutrophils treated with non-tumoral Evs. We also observed that neutrophils treated with MDA-Evs released increased IL-8, VEGF, MMP9, and increased expression of CD184, an N2-neutrophil marker. Finally, neutrophils treated with MDA-Evs increased tumor cell viability. Our results show that MDA-Evs induce an N2-like phenotype, and the blockage of phosphatidylserine by annexin-V may be an essential agent counter-regulating this effect.
免疫系统细胞，包括中性粒细胞，被肿瘤微环境招募作为慢性炎症的发生部位，并开始有利于肿瘤生长。存在于肿瘤部位的中性粒细胞称为肿瘤相关中性粒细胞（TAN），可呈现两种表型：N1（抗肿瘤）或 N2（促肿瘤）。有证据表明，免疫系统细胞与肿瘤细胞释放的细胞外囊泡（Evs）有很强的相互作用能力。Evs 可以调节免疫系统细胞的表型，促进肿瘤的发展。在这里，我们研究了 MDA-MB-231 衍生的 Evs 对中性粒细胞向 N2 表型极化的作用及其潜在机制。我们观察到，用 MDA 细胞释放的 Evs（MDA-Evs）处理的中性粒细胞半衰期延长，趋化能力增强，释放的 NETs 和 ROS 水平高于用非肿瘤性 Evs 处理的中性粒细胞。我们还观察到，用 MDA-Evs 处理的中性粒细胞释放的 IL-8、VEGF、MMP9 增加，N2 中性粒细胞标志物 CD184 的表达增加。最后，用 MDA-Evs 处理的中性粒细胞增加了肿瘤细胞的活力。我们的结果表明，MDA-Evs 诱导 N2 样表型，而 annexin-V 通过阻断磷脂酰丝氨酸可能是一种重要的拮抗这种作用的试剂。
