S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients

IF 9.1 1区 医学 Q1 ONCOLOGY Cancer letters Pub Date : 2024-10-09 DOI:10.1016/j.canlet.2024.217288
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Abstract

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.
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S100A7 可协调中性粒细胞趋化并推动中性粒细胞胞外捕获物 (NET) 的形成,从而促进宫颈癌患者的淋巴结转移。
中性粒细胞胞外捕获物(NET)已被证明能促进多种肿瘤的转移。我们的研究旨在探讨NETs在宫颈癌(CCa)淋巴结转移(LNM)中的作用和机制,并评估靶向NETs在CCa中的治疗价值。免疫组化结果表明,患有LNM的CCa患者中性粒细胞浸润和NETs形成增加,同时证实S100A7表达与CCa中性粒细胞浸润呈正相关。NETs通过与TLR2相互作用激活P38-MAPK/ERK/NFκB通路,从而增强了CCa的迁移能力。用脱氧核糖核酸酶1(DNase 1)消化NETs或用氯喹抑制TLR2可消除NETs诱导的CCa转移潜能。此外,NETs 还能促进淋巴管生成,增加淋巴管的通透性,从而促进 CCa 的跨淋巴运动。CCa衍生的S100A7对中性粒细胞有趋化作用,并通过提高ROS水平而不是激活中性粒细胞的自噬作用促进NET的生成。脚垫植入小鼠模型表明,DNase 1 能有效减少 LPS 诱导的小鼠和播种了 S100A7 高表达 CCa 细胞的小鼠的 LNM。总之,我们的研究揭示了S100A7新的促瘤机制,阐明了NETs在CCa LNM中的关键作用和机制,并指出NETs靶向疗法是一种很有前景的CCa抗转移疗法。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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