A novel oncotherapy strategy, direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer
A novel oncotherapy strategy, direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer
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直接凝血酶抑制剂是一种新型肿瘤治疗策略，可抑制非小细胞肺癌的进展、扩散和自发转移
DOI：
10.1111/bph.15384
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发表时间：
2021
影响因子：
7.3
通讯作者：
Mo Wo
中科院分区：
文献类型：
--
作者：
Zhao Bing;Wu Mengfang;Hu Zhihuang;Wang Tianfa;Yu Jinchao;Ma Yixin;Wang Qi;Zhang Yanling;Chen Di;Li Tianyu;Li Yaran;Yu Min;Wang Huijie;Mo Wo
背景和目的癌症恶病质和癌症相关血栓形成是晚期癌症潜在的致命后果。然而，凝血酶在非小细胞肺癌(NSCLC)原发肿瘤组织中的表达及其与NSCLC患者预后之间的关系尚不清楚。观察重组水蛭素和直接凝血酶抑制肽(DTIP)对肿瘤进展的影响。用Western blotting、免疫组织化学和免疫荧光等方法探讨r-水蛭素和DTIP的抑制作用机制。结果非小细胞肺癌组织中凝血酶的表达与临床病理特征及预后密切相关。凝血酶缺乏抑制了肿瘤的进展。新型凝血酶抑制剂r-水蛭素和DTIP在体外可抑制细胞的侵袭和转移。在原位肺癌模型中，它们抑制肿瘤的生长和转移，抑制细胞侵袭，并延长经尾静脉注射肿瘤细胞后的生存时间。它们还能抑制皮下接种肿瘤的血管生成和自发转移。在PAR-1缺陷的NSCLC细胞中，凝血酶对侵袭和转移的促进作用被取消。重组水飞蓟素和DTIP通过凝血酶-PAR-1介导的RhoA和NF-κB信号通路抑制MMP9和IL6的表达，从而抑制肿瘤的进展。DTIP增强化疗诱导的小鼠生长和转移抑制，并抑制化疗诱导的耐药性。结论和意义凝血酶与PAR-1一起，在NSCLC恶性肿瘤中起重要作用。抗凝剂r-水飞蓟素和DTIP可用于抗肿瘤治疗，DTIP联合化疗可提高疗效。
Background and PurposeCancer cachexia and cancer‐associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non‐small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown.Experimental ApproachClinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r‐hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r‐hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined.Key ResultsThrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r‐hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR‐1‐deficient NSCLC cells. r‐hirudin and DTIP inhibited tumour progression through the thrombin‐PAR‐1‐mediated RhoA and NF‐κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy‐induced growth and metastatic inhibition and inhibited chemotherapy‐induced resistance in mice.Conclusions and ImplicationsThrombin makes a substantial contribution, together with PAR‐1, to NSCLC malignancy. The anti‐coagulants, r‐hirudin and DTIP, could be used in anti‐tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.