Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability
Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability
复制标题
肿瘤特异性组织因子沉默可抑制转移并预防癌症相关的高凝状态
DOI：
10.1021/acs.nanolett.9b01785
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发表时间：
2019-07-01
期刊：
影响因子：
10.8
通讯作者：
Nie, Guangjun
中科院分区：
文献类型：
--
作者：
Liu, Shaoli;Zhang, Yinlong;Nie, Guangjun
在肿瘤内，凝血诱导蛋白组织因子(Tf)是血液凝固的主要起始者，由于其对肿瘤高凝状态的影响以及调节血小板与肿瘤细胞之间的相互作用，在肿瘤的血行转移中发挥着关键作用。因此，靶向肿瘤相关的转移因子在肿瘤患者的抗转移治疗和预防血栓并发症方面具有巨大的治疗潜力。在此，我们报道了一种新型的基于多肽的纳米颗粒，该纳米颗粒靶向肿瘤部位传递和释放小干扰RNA(SiRNA)，以沉默肿瘤相关转移因子的表达。我们的研究表明，抑制肿瘤细胞中TF的表达可以在体外阻断肿瘤细胞周围的血小板黏附。静脉注射肿瘤细胞(即模拟循环肿瘤细胞[CTCs])的TF表达下调，阻止了CTCs周围的血小板黏附，降低了CTCs在肺内的存活率。在乳腺癌小鼠模型中，含有siRNA的纳米颗粒有效地减弱了肿瘤微环境中TF的表达，并显著减少了实验性肺转移模型和荷瘤小鼠的肺转移量。更重要的是，这一策略通过减少凝血酶-抗凝血酶复合体(TAT)和活化的血小板的产生，扭转了荷瘤小鼠的高凝状态，这两种物质都是转移因子的下游产物。我们的研究描述了一种有希望的方法来对抗转移和预防癌症相关的血栓形成，这推动了转铁蛋白作为治疗靶点的临床应用。
Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hyper-coagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.