Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation

吉非替尼 血管生成拟态 凝血酶 肺癌 水蛭素 癌症研究 血栓调节蛋白 转移 医学 癌症 免疫学 病理 表皮生长因子受体 内科学 血小板
作者
Bing Zhao,Meng‐Fang Wu,Zhihuang Hu,Yixin Ma,Wang Qi,Yanling Zhang,Yaran Li,Min Yu,Huijie Wang,Wei Mo
出处
期刊:Signal Transduction and Targeted Therapy [Springer Nature]
卷期号:5 (1) 被引量:45
标识
DOI:10.1038/s41392-020-0167-1
摘要

Abstract Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition, which is characterized by vasculogenic mimicry (VM). VM not only accelerates tumor progression but also increases drug-induced resistance. However, very little is currently known about the molecular determinants that enable VM. Targeting VM might bring a new breakthrough in cancer treatment. Thrombin is the key enzyme of the blood coagulation system and could contribute to tumor progression. Nevertheless, the association between thrombin and VM formation remains largely unknown. We found that VM was associated with the overall survival of non-small-cell lung cancer (NSCLC) patients, and that thrombin expression was closely related to VM formation. This research revealed that thrombin induced VM formation via PAR-1-mediated NF-κB signaling cascades. The novel thrombin inhibitors r-hirudin and DTIP inhibited VM formation and spontaneous metastases in subcutaneous tumors. Clinical pathological analysis confirmed that NSCLC patients with thrombin-positive/PAR-1-high expression had the poorest prognosis and were the most likely to form VM. The promotional activity of thrombin in VM formation and tumor metastasis was abolished in PAR-1-deficient NSCLC cells. The EGFR inhibitor gefitinib had no effect on VM and increased VEGF expression in tumors. The combination therapy of DTIP and gefitinib achieved a better therapeutic effect than either agent alone. This study is the first to illustrate that thrombin substantially contributes, together with PAR-1, to VM formation and to illustrate that VM might be a target of r-hirudin and DTIP to suppress tumor progression. The anticoagulants r-hirudin and DTIP could be employed for antitumor therapy. Combination therapy with DTIP with an EGFR inhibitor might achieve superior therapeutic effects.
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