Platelet TLR4-ERK5 Axis Facilitates NET-Mediated Capturing of Circulating Tumor Cells and Distant Metastasis after Surgical Stress.
Platelet TLR4-ERK5 Axis Facilitates NET-Mediated Capturing of Circulating Tumor Cells and Distant Metastasis after Surgical Stress.
复制标题
血小板 TLR4-ERK5 轴促进 NET 介导的循环肿瘤细胞捕获和手术应激后的远处转移
DOI：
10.1158/0008-5472.can-20-3222
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发表时间：
2021-05-01
期刊：
影响因子：
11.2
通讯作者：
Tsung A
中科院分区：
文献类型：
--
作者：
Ren J;He J;Zhang H;Xia Y;Hu Z;Loughran P;Billiar T;Huang H;Tsung A
通过 TLR4/ERK5/整合素 GPIIb/IIIa 信号传导靶向血小板激活显示出预防切除后患者 NET 驱动的远处转移的潜力。手术切除恶性肿瘤是控制大多数实体癌症的主要手段。然而，手术损伤也会增加肿瘤复发和转移的风险。组织创伤会局部和全身激活先天免疫系统，引发炎症反应。血小板和中性粒细胞是治愈组织的早期先天免疫反应中的两个关键参与者，但它们的作用也可能有助于癌细胞扩散和远处转移。在这里，我们报告手术应激激活的血小板增强了血小板-肿瘤细胞聚集体的形成，促进它们被中性粒细胞胞外陷阱（NET）捕获并随后发生远处转移。局部手术应激的小鼠肝缺血/再灌注 (I/R) 损伤模型表明，I/R 促进 NET 捕获聚集的循环肿瘤细胞 (CTC)，并最终转移至肺部，而当血小板耗尽时，这种转移会被消除。肝脏 I/R 还增加了肺微脉管系统内 NET 的沉积，但血小板的消耗没有影响。 TLR4 以 ERK5-GPIIb/IIIa 整合素依赖性方式对血小板活化和血小板-肿瘤细胞聚集体形成至关重要。这种聚集促进了静态和动态条件下体外 CTC 的 NET 介导捕获。阻断血小板活化或敲除 TLR4 可保护小鼠免受 I/R 诱导的肝转移，并且 NET 不会捕获 CTC。这些结果揭示了血小板和中性粒细胞在急性炎症情况下促进转移的新机制。有针对性地破坏血小板和 NET 之间的相互作用有望预防术后远处转移。意义：通过 TLR4/ERK5/整合素 GPIIb/IIIa 信号传导靶向血小板激活显示出预防切除后患者 NET 驱动的远处转移的潜力。
Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection. Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress–activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent postoperative distant metastasis. Significance: Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection.