Role of deformable cancer cells on wall shear stress-associated-VEGF secretion by endothelium in microvasculature

Mahsa Dabagh,Amanda Randles,Juan Carlos Del Alamo

doi:10.1371/journal.pone.0211418

Abstract

Endothelial surface layer (glycocalyx) is the major physiological regulator of tumor cell adhesion to endothelium. Cancer cells express vascular endothelial growth factor (VEGF) which increases the permeability of a microvessel wall by degrading glycocalyx. Endothelial cells lining large arteries have also been reported, in vitro and in vivo, to mediate VEGF expression significantly under exposure to high wall shear stress (WSS) > 0.6 Pa. The objective of the present study is to explore whether local hemodynamic conditions in the vicinity of a migrating deformable cancer cell can influence the function of endothelial cells to express VEGF within the microvasculature. A three-dimensional model of deformable cancer cells (DCCs) migrating within a capillary is developed by applying a massively parallel hemodynamics application to simulate the fluid-structure interaction between the DCC and fluid surrounding the DCC. We study how dynamic interactions between the DCC and its local microenvironment affect WSS exposed on endothelium, under physiological conditions of capillaries with different diameters and flow conditions. Moreover, we quantify the area of endothelium affected by the DCC. Our results show that the DCC alters local hemodynamics in its vicinity up to an area as large as 40 times the cancer cell lateral surface. In this area, endothelium experiences high WSS values in the range of 0.6–12 Pa. Endothelial cells exposed to this range of WSS have been reported to express VEGF. Furthermore, we demonstrate that stiffer cancer cells expose higher WSS on the endothelium. A strong impact of cell stiffness on its local microenvironment is observed in capillaries with diameters <16 μm. WSS-induced-VEGF by endothelium represents an important potential mechanism for cancer cell adhesion and metastasis in the microvasculature. This work serves as an important first step in understanding the mechanisms driving VEGF-expression by endothelium and identifying the underlying mechanisms of glycocalyx degradation by endothelium in microvasculature. The identification of angiogenesis factors involved in early stages of cancer cell-endothelium interactions and understanding their regulation will help, first to develop anti-angiogenic strategies applied to diagnostic studies and therapeutic interventions, second to predict accurately where different cancer cell types most likely adhere in microvasculature, and third to establish accurate criteria predisposing the cancer metastasis.

Highlights

Adhesion of deformable cancer cells (DCCs) to vascular endothelium is a critical stage of metastasis that precedes the invasion and extravasation of DCC [1,2,3]
The motion of deformable spheres in a cylinder has been extensively studied in the literature [16,17,18,19,20,21,22,23,24,25,26,27,28,29], but there are unaddressed issues that constitute our main framework in this paper as follows: a) Earlier studies have focused on exploring the effect of hemodynamics on the motion and deformation of a sphere, whereas we have diverted our attention to how a deformable sphere influences the hemodynamic characteristics on neighboring regions of endothelium; b) Unlike earlier studies, we have identified the linkage between the location/ properties of the sphere and the measured Wall shear stress (WSS) over the capillary wall surface; and c) We have located the sphere near the capillary wall whereas it was located at the center of the capillary cylinder, in other studies [16,17,18,19,20,21,22,23,24,25,26,27,28,29]
We have investigated the mechanisms underlying wall shear stress-associated-vascular endothelial growth factor (VEGF) secretion by endothelium which may contribute to the degradation of the glycocalyx layer in the stage prior to the adhesion of tumor cells to microvessel walls

Summary

Introduction

Adhesion of deformable cancer cells (DCCs) to vascular endothelium is a critical stage of metastasis that precedes the invasion and extravasation of DCC [1,2,3]. It has previously shown that DCC facilitates its own adhesion to the endothelium by secreting vascular endothelial growth factor (VEGF) that locally degrades the glycocalyx layer, resulting in the exposure of endothelial adhesion molecules [1,2,3,4,5]. Wall shear stress (WSS), the hemodynamic traction force, has been shown, in vivo, to contribute in VEGF expression by endothelial cells in the range of physiological arterial blood flow (0.6–4 Pa) [7]. The presence of DCC in microvasculature can be a key factor in altering WSS in the vicinity of DCC which can influence the function of endothelial cells to express VEGF. The study of the role of DCC in altering WSS in its vicinity in a microvessel is the focus of this work

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