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

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.

Fig 1. Schematic illustration of a cancer cell circulating in vicinity of endothelial surface glycocalyx.

A) Cancer cell in vicinity of endothelial surface glycocalyx. B) Receptors on a substrate and ligands on a membrane. The glycocalyx layer is anchored on the endothelial cell surfaces.

Fig 2. Comparison between current results and Lefebvre at el., for the shape of deformable, cancer cell migrating freely in a capillary when Dc/Dv = 0.77.

Note that cell is located at the center of the capillary. Rv stands for the vessel radius. Z is the flow direction.

Fig 3. Aspect ratio of a deformable cancer cell migrating within microvasculature.

The diameter of capillaries varies in the range of 8.82–16 μm. A) γ = 125 s^-1. B) γ = 312 s^-1.

Fig 4. State diagram of a deformable cancer cell motion in capillaries as the function of capillary number Ca and normalized capillary diameter (Dc/Dv).

Filled squares represent rolling motion of the cell and open squares correspond to bullet motion.

Fig 5. The distribution of WSS over endothelium.

A) Dc/Dv = 0.907 and γ = 312 s^-1. B) Dc/Dv = 0.667 and γ = 312 s^-1. C) Dc/Dv = 0.5 and γ = 312 s^-1. Note that shear elastic modulus of the cancer cell is 30 N/m in all panels of Fig 5.

Fig 6. Maximum magnitude of WSS over endothelium in the vicinity of circulating cancer cell.

Cells with different stiffnesses are migrating within capillaries with diameters varying in the range of 8.82–16 μm. A) γ = 125 s^-1. B) γ = 312 s^-1.

Fig 7. Local changes to hemodynamics nearby a deformable, circulating cancer cell.

The area of endothelium, A_aff, (characteristic affected area) in the vicinity of cancer cell (with WSS > 0.6 Pa) is demonstrated. A_DCC is lateral surface of the cancer cell. Note that cancer cells with different stiffnesses are migrating within capillaries with diameters varying in the range of 8.82–16 μm. A) γ = 125 s^-1. B) γ = 312 s^-1.