绑定细胞微粒的VWF在微粒介导胃癌细胞跨内皮迁移中的作用： 一种肿瘤转移的新机制

We have recently reported that the adhesive ligand von Willebrand factor (VWF) is synthesized and released from primary and clonal gastric cancer cells and promotes blood-derived gastric cancer metastasis. Our preliminary data further show that the ability of cellular microparticles (MPs) to disrupt the endothelial integrity is significantly enhanced by MPs-bound and hyperadhesive VWF by facilitating MP binding to endothelial cells. These novel observations have led us to hypothesize that 1) VWF released from cancer cells is hyperadhesive and becomes microparticle-bound to stimulate platelets and endothelial cells to produce more MPs and VWF, propagating and amplifying the process of microvesiculation, 2) the hyperadhesive VWF binds MPs of various cell origins to enhance their activity in disrupting the endothelium and promoting cancer metastasis, and 3) enhancing MPs clearance or reducing VWF adhesive activity could reduce blood-derived cancer metastasis. To test these hypotheses, we propose to comprehensively investigate a role of VWF in the MP-mediated transendothelial migration and metastasis of gastric cancer cells by conducting in vitro experiments, studying mouse models, and analyzing VWF activity in patients with gastric cancer. These complementary experiments could define synergistic activities between VWF and MPs in mediating gastric cancer metastasis.

我们最近报道：原发胃癌细胞及胃癌细胞克隆株均能产生并释放黏附分子配体VWF，促进胃癌的血道转移。我们的初步数据进一步显示绑定细胞微粒（MPs）的高活性VWF可以介导MPs与内皮细胞的连接，从而增强MPs破坏内皮屏障完整性的能力。据此我们假设：1）肿瘤患者血浆VWF是高粘附活性的，并绑定细胞微粒，包括肿瘤细胞微粒（TMPs）；2）这种高粘附活性的VWF介导TMPs激活血小板和内皮细胞，使其产生更多的MPs和VWF，从而增强MPs破坏内皮屏障和促进肿瘤转移的能力；3）降低VWF的粘附活性或增加细胞微粒的清除能够减少肿瘤血道转移的发生。据此本项目以我国西部高发胃癌为研究对象，分析VWF活性与胃癌患者转移率等临床病理因素的相关性，通过建立小鼠肿瘤模型等体内外实验，明确VWF和MPs在介导肿瘤转移中的协同作用，为肿瘤转移机制研究提供新思路。

循环中的肿瘤源性细胞外囊泡可破坏内皮屏障的完整性、从而促进循环肿瘤细胞游出血管外形成转移灶，与胃腺癌患者血浆中升高的VWF水平之间的关系，是否通过EVs bound VWF发挥增加破坏内皮屏障促进转移的作用，机制仍然不清。我们通过临床样本、体外实验与小鼠模型研究发现，胃癌患者血浆存在高黏附活性的VWF并绑定EVs，与胃癌患者临床病理因素和预后相关，可作为诊断及预后指标；胃癌细胞源性细胞外囊泡（gcEVs）可活化内皮并释放VWF，介导促进gcEVs破坏血管屏障、增加内皮通透性，促进肿瘤细胞跨内皮迁移；联合ADAMTS-13与Lactadherin能够减少小鼠胃癌血道转移的发生。该研究结果揭示了EVs bound VWF可能是胃癌临床诊断、预后分析、治疗干预的新思路和方向。

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