Yang Ai-Jun, Wang Min, Wang Yan, Cai Wei, Li Qiang, Zhao Ting-Ting, Zhang Li-Han, Houck Katie, Chen Xu, Jin Yan-Ling, Mu Ji-Ying, Dong Jing-Fei, Li Min
Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Oncogenesis. 2018 Jan 24;7(1):12. doi: 10.1038/s41389-017-0023-5.
Cancer prognosis is poor for patients with blood-borne metastasis. Platelets are known to assist cancer cells in transmigrating through the endothelium, but ligands for the platelet-mediated cancer metastasis remain poorly defined. von Willebrand factor (vWF) is a major platelet ligand that has been widely used as a biomarker in cancer and associated inflammation. However, its functional role in cancer growth and metastasis is largely unknown. Here we report that gastric cancer cells from patients and cells from two well-established gastric cancer lines express vWF and secrete it into the circulation, upon which it rapidly becomes cell-bound to mediate cancer-cell aggregation and interaction with platelets and endothelial cells. The vWF-mediated homotypic and heterotypic cell-cell interactions promote the pulmonary graft of vWF-overexpressing gastric cancer BGC823 cells in a mouse model. The metastasis-promoting activity of vWF was blocked by antibodies against vWF and its platelet receptor GP Ibα. It was also reduced by an inhibitory siRNA that suppresses vWF expression. These findings demonstrate a causal role of cancer-cell-derived vWF in mediating gastric cancer metastasis and identify vWF as a new therapeutic target.
血行转移患者的癌症预后较差。已知血小板可协助癌细胞穿过内皮细胞迁移，但血小板介导的癌症转移的配体仍不清楚。血管性血友病因子（vWF）是一种主要的血小板配体，已被广泛用作癌症及相关炎症的生物标志物。然而，其在癌症生长和转移中的功能作用在很大程度上尚不清楚。在此，我们报告来自患者的胃癌细胞以及来自两个成熟胃癌细胞系的细胞表达vWF并将其分泌到循环中，随后它迅速与细胞结合，介导癌细胞聚集以及与血小板和内皮细胞的相互作用。在小鼠模型中，vWF介导的同型和异型细胞间相互作用促进了过表达vWF的胃癌BGC823细胞的肺移植。针对vWF及其血小板受体糖蛋白Ibα的抗体可阻断vWF的促转移活性。抑制vWF表达的小干扰RNA也可降低其活性。这些发现证明了癌细胞来源的vWF在介导胃癌转移中的因果作用，并将vWF确定为一个新的治疗靶点。
