血管内皮屏障完整性是影响肿瘤细胞跨内皮迁移、导致肿瘤血道转移的关键。研究发现外周血肿瘤细胞微粒（TMPs）和血小板微粒（PMPs）水平随肿瘤进展增高，但其能否通过影响血管内皮通透性促进肿瘤转移，目前尚未见报道。我们前期研究发现小鼠肝癌细胞微粒能促进肿瘤转移、体内诱导血管高通透性；胃癌细胞微粒体外可诱导内皮通透性增加。我们推测：肿瘤细胞微粒可能通过激活血管内皮，介导肿瘤细胞与内皮粘附；增加内皮通透性，促进肿瘤细胞跨内皮迁移，导致肿瘤血道转移。据此本项目以我国西部高发胃癌为研究对象，应用微流体技术、跨内皮电阻测定、Transwell迁移模型、Nanodiscs、质谱分析、移植瘤和小动物成像等技术，进一步探讨TMPs对血管内皮屏障的影响；阐明TMPs结构完整性、VEGFA-VEGFR2-VE-cadherin信号通路及血小板微粒与TMPs介导内皮屏障损伤的相关性，为肿瘤转移机制研究提供新思路。

The integrity of vascular endothelial barrier is critical for transmigrating through the endothelium and promoting distant metastasis for tumor cells. Studies reported that tumor-derived microparticles (TMPs) and platelet-derived microparticles (PMPs) were increased with tumor progression, but whether they could promote tumor metastasis by influencing the permeability of vascular endothelial had not been reported. Our previous data showed that the hematogenous metastasis of hepatic carcinoma was promoted by mice hepatocellular carcinoma cells derived microparticles, which was rich in vascular permeability factor VEGFA, it induced high capillary permeability of capillaries in mice. In addition, the gastric cells derived microparticles in vitro increased the permeability of vascular endothelial. These data and the published reports have led us to hypothesize that TMPs may promote hematogenous metastasis by activating vascular endothelial, promoting cancer cells to adhere and transmigrate through the endothelium and increaseing the permeability of vascular endothelial. We will test these hypotheses by achieving three specific aims. First, we chose to study gastric cancer because it has a higher incidence the western region, including Gansu than other parts of China. Second, we will use Nanodiscs, microfluidic technology, measurement of electrical resistance across endothelial cell monolayers, Transwell migration model, mass spectrometry, xenograft and small animal imaging in vivo to explore the effects of TMPs on vascular endothelial barrier. Third, we will define that the role of the structural integrity of TMPs, VEGFA-VEGFR2-VE-cadherin signaling pathways and synergy with PMPs in endothelial barrier disruption that is induced by TMPs. Together, these studies are designed to identify the mechanisms in promoting cancer hematogenous metastasis, new diagnostic/prognostic biomarkers, and novel therapeutics.