Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation
Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation
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凝血酶是非小细胞肺癌的治疗靶点，可抑制血管生成拟态形成
DOI：
10.1038/s41392-020-0167-1
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发表时间：
2020-07-10
影响因子：
39.3
通讯作者：
Mo, Wei
中科院分区：
文献类型：
--
作者：
Zhao, Bing;Wu, Mengfang;Mo, Wei
肿瘤细胞通过上皮-间质转化转化为内皮细胞，其特征是血管生成拟态（VM）。 VM不仅加速肿瘤进展，而且增加药物诱导的耐药性。然而，目前人们对 VM 的分子决定因素知之甚少。针对VM可能会给癌症治疗带来新的突破。凝血酶是凝血系统的关键酶，可能有助于肿瘤进展。然而，凝血酶和 VM 形成之间的关联仍然很大程度上未知。我们发现VM与非小细胞肺癌（NSCLC）患者的总生存期相关，并且凝血酶的表达与VM的形成密切相关。这项研究表明，凝血酶通过 PAR-1 介导的 NF-κB 信号级联诱导 VM 形成。新型凝血酶抑制剂 r-水蛭素和 DTIP 可抑制皮下肿瘤中 VM 的形成和自发转移。临床病理分析证实，凝血酶阳性/PAR-1高表达的NSCLC患者预后最差，最容易形成VM。在 PAR-1 缺陷的 NSCLC 细胞中，凝血酶对 VM 形成和肿瘤转移的促进活性被消除。 EGFR 抑制剂吉非替尼对 VM 没有影响，但会增加肿瘤中 VEGF 的表达。 DTIP与吉非替尼联合治疗比单独使用任一药物取得了更好的治疗效果。这项研究首次证明了凝血酶与 PAR-1 一起对 VM 的形成有重大贡献，并证明 VM 可能是 r-水蛭素和 DTIP 抑制肿瘤进展的靶点。抗凝剂r-水蛭素和DTIP可用于抗肿瘤治疗。 DTIP 与 EGFR 抑制剂的联合治疗可能会取得更好的治疗效果。
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.