血小板Shp2调控肿瘤相关血栓形成的机制解析和实验性干预研究

肿瘤相关性血栓是常见的癌症相关性疾病，已成为癌症患者的主要死亡原因。血小板是调控血栓发生的关键细胞，在癌症患者血栓栓塞发生中起主导作用。临床上以抗凝机制为靶点防治肿瘤相关性血栓，但疗效有限，长期使用还会导致出血倾向增加。因此，深入研究肿瘤细胞引起血小板活化的主要机制，能为改善肿瘤相关性血栓的防治提供有效依据。前期实验结果推测酪氨酸磷酸酶Shp2极有可能是特异性调控肿瘤引起的血小板活化的关键分子，Shp2缺失影响由肿瘤细胞引起的血小板聚集和释放。蛋白质组学和免疫共沉淀数据提示，Shp2通过与CLEC-2受体下游Syk，SKAP2，14-3-3等分子结合参与Syk介导的信号转导。故本研究将基于这些发现，进一步明确Shp2在肿瘤细胞引起的血小板活化以及血栓形成中的作用;Shp2参与调控肿瘤细胞引起的血小板活化的具体机制；筛选能有效抑制由肿瘤细胞引起的血小板活化和血栓形成的Shp2小分子抑制剂。

Tumor-associated thrombus is a common cancer-related disease and has become the leading cause of death in cancer patients. Platelets are key cells that regulate thrombogenesis and play a leading role in the development of thromboembolism in cancer patients. Clinically, anticoagulation mechanism is used as the target to prevent and treat tumor-related thrombus, but the efficacy is limited, and long-term use will also lead to increased bleeding tendency. Therefore, in-depth study of the main mechanism of platelet activation induced by tumor cells can provide an effective basis for improving the prevention and treatment of tumor-related thrombus.Preliminary results suggested that tyrosine phosphatase Shp2 may be a key molecule for specific regulation of tumor-induced platelet activation.Shp2 deficiency affected platelet aggregation and release induced by tumor cells. Platelet proteomics and immunoco-precipitation data suggest that Shp2 binds with downstream molecules of clec-2 receptor such as Syk, SKAP2, 14-3-3, etc. to participate in Syk-mediated signal transduction. Therefore, based on these findings, this study will further clarify the role of Shp2 in platelet activation and thrombogenesis induced by tumor cells. And clarify the specific mechanism by which Shp2 is involved in the regulation of platelet activation induced by tumor cells; Screening for Shp2 inhibitors that effectively inhibit tumor-induced platelet activation and thrombus.