TWEAK介导的SphK/S1P通路在卵巢癌血管生成中的作用及机制研究

Angiogenesis is critical to growth, metastasis and ascites development in epithelial ovarian cancer (EOC), and is associated with its poor prognosis. Therefore, it has important significance to uncover the mechanisms of EOC angiogenesis. We previously reported that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is overexpressed in ovarian cancer tissue and is involved in promoting vascular endothelial growth factor (VEGF) secretion from EOC cells. Besides, we found for the first time in our pre-experiment that TWEAK could activate sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway in EOC. Moreover, it has been reported that both TWEAK and SphK/S1P play important roles in angiogenesis. Thus, we hypothesized that TWEAK mediated SphK/S1P activation might be one of the critical pathways in EOC angiogenesis. This study, performed using patient tissue samples, cell and animal models, will investigate the relationship between TWEAK, SphK/S1P and EOC angiogenesis, uncover the role of TWEAK mediated SphK/S1P activation in EOC angiogenesis and its related mechanisms, and examine the effect of TWEAK and/or SphK/S1P targeted therapies on EOC angiogenesis. Our study may provide new targets for ovarian cancer treatment.

血管生成在上皮性卵巢癌（EOC）的生长、转移、腹水形成过程中起关键作用，并与EOC预后不良密切相关。因此，阐明EOC血管生成机制对其临床治疗具有重要意义。我们在前期研究中发现TWEAK在EOC组织中高表达，并能促进EOC细胞分泌血管内皮生长因子。此外，我们在预实验中首次发现TWEAK能够激活EOC细胞的SphK/S1P通路。结合文献报道TWEAK和SphK/S1P均可在血管生成过程中发挥重要作用，我们推测TWEAK介导的SphK/S1P激活可能是调控EOC血管生成的关键性通路之一。本课题将首次通过病例研究、体外细胞培养和体内动物实验探索TWEAK、SphK/S1P与EOC血管生成的关系；检测TWEAK是否通过调控SphK/S1P通路来影响EOC的血管生成及其相关机制；研究调控TWEAK表达和/或SphK/S1P通路活性在抑制EOC血管生成中的作用，为卵巢癌的靶向治疗提供理论依据。

本研究项目拟通过免疫组化、细胞学实验以及动物模型等实验方法明确SphK/S1P 信号通路在卵巢癌血管生成中的机制。为此，我们深入细致地从患者标本、卵巢癌细胞和动物模型等多方面对该通路调控卵巢癌血管生成的机制进行探索和分析。通过三年的工作，已经成功地证明了以下科学事实：第一：SphK1在卵巢癌中过表达，并且其表达水平与卵巢癌组织的微血管密度(MVD)呈正相关。第二：在体外模型中，抑制SphK1能够抑制卵巢癌细胞的体外促血管生成能力和促血管生成因子的分泌水平。且这种现象能够被反向添加S1P所抑制。另外，S1P能够通过S1PR1/3促进卵巢癌细胞分泌促血管生成因子。此外，抑制S1PR1/3能够抑制卵巢癌细胞的体外促血管生成能力和促血管生成因子的分泌水平。第三：在体内模型中，抑制SphK1或S1PR1/3能够抑制卵巢癌组织的血管生成和促血管生成因子的表达水平。由此，我们发现了SphK1/S1P/S1PR1/3轴在卵巢癌中的新作用，该信号轴可能成为卵巢癌抗血管治疗的新靶点。