Unveiling the Impact of Hemodynamics on Endothelial Inflammation-mediated Hepatocellular Carcinoma Metastasis Using a Biomimetic Vascular Flow Model.

Distant metastasis of hepatocellular carcinoma (HCC) mediated by hematogenous dissemination is a leading cause of HCC-related deaths. The inflammatory response of vascular endothelial cells facilitates this process by promoting the adhesion and invasion of tumor cells in the circulatory system. While the regulation of this inflammation-mediated metastasis through upregulation of adhesion molecules and disruption of intercellular junctions has been well established, the contribution of hemodynamics to this process remains poorly understood due to the lack of a suitable vascular flow model for investigation. In this study, we developed a vascular flow model with shear stress ranging from 0-6 dyn/cm 2 , which can mimic physiological blood flow conditions of small and medium vessels, to examine the impact of hemodynamics on endothelial inflammation-mediated HCC metastasis. We found a significant negative correlation between HCC cells adhesion and shear stress loading during the fluid perfusion, the increasing shear stress will reduce the recruitment of HCC cells by disturbing adhesion forces between endothelium and HCC cells. However, this reduction will be restored by the inflammation. When applying high FSS (4-6 dyn/cm 2 ) to the inflammatory endothelium, there will be a 4.8-fold increase in HCC cell adhesions compared to normal condition. Nevertheless, the increase fold of cell adhesions is inapparent, around 1.5-fold, with low and medium FSS. This effect can be attributed to the FSS-induced upregulation of ICAM-1 and VCAM-1 of the inflammatory endothelium, which serve to strengthen cell binding forces. The suppression of adhesion-related factors by K7174 hinders the recruitment ability of vascular endothelial cells towards HepG2 cells. These findings indicate that hemodynamics plays a key role in HCC metastasis during endothelial inflammation by regulating the expression of adhesion-related factors. This article is protected by copyright. All rights reserved.