循环组织因子阳性膜微粒在肺癌相关静脉血栓栓塞症发生中的作用

Lung cancer is one of the most common malignancies easily complicated with venous thromboembolism (VTE).Circulating tissue factor-positive microparticles (TF+MPs) are important procoagulants for cancers. Oncogene signal pathways are involved in the abnormal expression of tissue factor. Our preliminary study showed that circulating TF+MPs significantly increased in lung cancer patients with VTE and occurrence of VTE was related with KRAS gene mutation. How do the circulating TF+MPs influence on the function of coagulation to result in thrombosis in lung cancer? Why do the circulating TF+MPs significantly increase in some cancers? On these ground, we make a hypothesis that the activation of some oncogenes (such as KRAS gene) increase the circulating tumor-derived TF+MPs, which activate coagulation and enhance thrombosis in lung cancer. We will investigate the role of TF+MPs in coagulation and thrombosis through screened non-small cell lung cancer cell lines with the high and low expressions of tissue factor, mice lung cancer model and deep venous thrombosis model of mice with lung cancer, also the signal pathways related with TF+MPs expression is explored. Our research will be helpful in exploring the pathogenesis of VTE associated with lung cancer and new target in prevention and treatment of VTE in lung cancer.

肺癌是最常见易并发静脉血栓栓塞症的恶性肿瘤之一。循环组织因子阳性膜微粒（tissue factor-positive microparticles, TF+MPs)是促进肿瘤高凝的重要物质，癌基因信号通路参与组织因子的表达调控。我们前期研究表明：肺癌合并静脉血栓的患者，循环TF+MPs数量显著增多；静脉血栓发生与KRAS基因突变相关。TF+MPs是如何影响肺癌凝血致血栓形成？为什么循环TF+MPs 数量增多？目前尚无研究报道。我们假设KRAS等癌基因的激活导致循环肿瘤源性TF+MPs增多， TF+MPs通过激活凝血促进血栓形成。我们拟筛选高/低表达组织因子的肺癌细胞系，建立肺癌小鼠模型和肺癌小鼠深静脉血栓模型，分析循环TF+MPs对凝血和静脉血栓形成的作用，探讨影响肿瘤源性TF+MPs表达的信号通路。本研究着眼于肿瘤微环境，深入认识肺癌相关静脉血栓栓塞症的发生机制，为其防治提供新的靶点。

静脉血栓栓塞症是肺癌常见的合并症和猝死原因。其发生的危险因素包括患者、肿瘤和治疗三个方面。本研究首先探讨了患者心血管相关危险因素和肿瘤分子亚型（EGFR、KRAS、ALK）与肺癌相关静脉血栓栓塞症的关系。进一步探讨表明，循环组织因子阳性膜微粒（tissue factor positive microparticles, TF+MPs）是促进肺癌高凝的重要物质。其表达与常见的TF+5466A/G、TFPI-287T/C和TFPI-33T/C 三个单核苷酸多态性改变无关，与KRAS基因突变无显著相关，可能与EGFR基因突变或ALK基因重排有关。本研究着眼于循环中TF+MPs的作用，进一步探讨了肺癌相关静脉血栓栓塞症的发生机制，为其防治提供新的靶点。