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.

Impact of Wound Dressing on Mechanotransduction within Tissues of Chronic Wounds

“…Mechanotransduction and its role in the progression of other diseases (e.g., atherosclerotic cardiovascular diseases and cancer) has been intensely studied [ 14 , 15 , 16 , 17 , 37 , 38 , 39 , 40 , 41 , 42 ]. Dabagh et al [ 42 , 43 , 44 ] have studied mechanotransduction in endothelial cells to elucidate mechanisms involved in progression of atherosclerotic cardiovascular diseases and cancer metastasis. In this study, we take the first steps to understand how mechanotransduction can enhance our understanding of chronic wounds’ healing process and mechanisms underlying the healing of these wounds.…”

A Hybrid Continuum-Particle Approach for Fluid-Structure Interaction Simulation of Red Blood Cells in Fluid Flows

“…Therefore, our proposed approach can be applied for many biomedical applications such as estimating the fluctuations of RBC membrane [19], thrombus formation, and blood clots [30,31]. Our results also suggest that this hybrid methodology can be extended for a variety of cells in physiological conditions such as the dynamics of white blood cells, platelets, or cancer cells [35]. Our future works will extend the current framework to be applicable for such situations.…”

“…In this type of coupling, fluid plasma can be described separately from the cell membrane model. For example, the Lattice Boltzmann Immersed Boundary method has also been developed [31,34,35]. In this model, the Lattice Boltzmann Method (LBM) [2], a particlebased method, is used to simulate the fluid plasma while the DPD or Finite Element model is used for the cell membrane.…”

Epigenetic modification regulates tumor progression and metastasis through EMT (Review)

“…After cell extravasation, CTCs need to create specific conditions to reach the target organs ( 27 ). The steps of cancer cells exiting the vessel wall are opposite to the direction of their entering the vessel wall ( 28 ). Cancer cells removed from blood vessels are in an unfavorable environment, and they have to overcome various difficulties to establish metastases ( 29 ).…”