The Roles of Platelet GPIIb/IIIa and αvβ3 Integrins during HeLa Cells Adhesion, Migration, and Invasion to Monolayer Endothelium under Static and Dynamic Shear Flow

Abstract

During their passage through the circulatory system, tumor cells undergo extensive interactions with various host cells including endothelial cells and platelets. Mechanisms mediating tumor cell adhesion, migration, and metastasis to vessel wall under flow condition are largely unknown. The aim of this study was to investigate the potential roles of GPIIb/IIIa and αvβ3 integrins underlying the HeLa-endothelium interaction in static and dynamic flow conditions. HeLa cell migration and invasion were studied by using Millicell cell culture insert system. The numbers of transmigrated or invaded HeLa cells significantly increased by thrombin-activated platelets and reduced by eptifibatide, a platelet inhibitor. Meanwhile, RGDWE peptides, a specific inhibitor of αvβ3 integrin, also inhibited HeLa cell transmigration. Interestingly, the presence of endothelial cells had significant effect on HeLa cell migration regardless of static or cocultured flow condition. The adhesion capability of HeLa cells to endothelial monolayer was also significantly affected by GPIIb/IIIa and αvβ3 integrins. The arrested HeLa cells increased nearly 5-fold in the presence of thrombin-activated platelets at shear stress condition (1.84 dyn/cm2 exposure for 1 hour) than the control (static). Our findings showed that GPIIb/IIIa and αvβ3 integrins are important mediators in the pathology of cervical cancer and provide a molecular basis for the future therapy, and the efficient antitumor benefit should target multiple receptors on tumor cells and platelets.