血管生成是肿瘤生长转移的关键条件。血管生成拟态（vasculogenic mimicry，VM）与患者预后密切相关，但目前抗血管生成药物主要以抑制内皮细胞依赖性血管生成为基础，忽略了VM的存在。前期工作发现凝血酶可以促进肺癌VM形成，但凝血酶在VM中的作用机制还未见相关报道。PAR-1是凝血酶主要受体，我们推测凝血酶通过激活PAR-1，促进上皮间质转化，促进VM形成。本课题拟开展以下研究：1.收集人肺癌标本，明确凝血酶、PAR-1、VM及预后之间的关系，揭示其临床意义；2.在细胞和分子水平研究凝血酶对肺癌VM形成的作用及分子机制；3.通过小鼠肺癌模型研究直接凝血酶抑制剂短肽（DTIP）和重组水蛭素（r-hirudin）对VM的作用机制及与抗内皮细胞依赖性血管药物联用对肺癌发生发展的作用。通过此研究明确凝血酶对VM形成的作用和机制，为直接凝血酶抑制剂拓展为抗肿瘤治疗以及联合用药提供理论基础。

Angiogenesis is a key condition for tumor growth and metastasis. Vasculogenic mimicry (VM) is closely associated with poor prognosis of tumor patients. However, the current anti-angiogenic drugs are mainly based on the inhibition of endothelial cell-dependent angiogenesis, ignoring the existence of VM. Our previous work found that thrombin could promote the formation of VM in lung cancer, but the role and mechanism of thrombin in vasculogenic mimicry have not been reported. PAR-1 is the main receptor of thrombin. It is speculated that thrombin promotes epithelial mesenchymal transformation by activating PAR-1, thereby promoting the formation of VM. This subject intends to carry out the following research: 1. Human lung cancer specimens were collected to clarify the relationship between thrombin, PAR-1, VM and prognosis of patients, so as to reveal their clinical significance. 2. To study the effect and molecular mechanism of thrombin on the formation of VM in lung cancer at the cellular and molecular levels; 3. The effects of DTIP and r-hirudin on VM of lung cancer and the combined use of anti-endothelial cell-dependent vascular drugs on the development of lung cancer were studied in a mouse tumor model. Through this study, the role and mechanism of thrombin in VM formation were clarified, which provided a theoretical basis for the development of direct thrombin inhibitors for anti-cancer therapy and combination with anti-endothelial cell dependent vascular drugs.