Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
PLoS One. 2019 Feb 22;14(2):e0211418. doi: 10.1371/journal.pone.0211418. eCollection 2019.
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.
内皮表面层（糖萼）是肿瘤细胞黏附在内皮细胞上的主要生理调节剂。癌细胞表达血管内皮生长因子（VEGF），通过降解糖萼增加微血管壁的通透性。据报道，在体外和体内，大动脉内皮细胞在暴露于大于 0.6 Pa 的高壁面切应力（WSS）下，也能显著介导 VEGF 的表达。本研究的目的是探讨迁移变形癌细胞附近的局部血液动力学条件是否会影响内皮细胞在微血管中表达 VEGF 的功能。通过应用大规模并行血液动力学应用程序，建立了变形癌细胞（DCC）在毛细血管内迁移的三维模型，以模拟 DCC 与 DCC 周围流体之间的流固相互作用。我们研究了 DCC 与其局部微环境之间的动态相互作用如何影响不同直径和流动条件下毛细血管内皮细胞暴露的 WSS。此外，我们量化了受 DCC 影响的内皮细胞面积。研究结果表明，DCC 会改变其附近的局部血液动力学，其影响范围可达癌细胞侧向表面积的 40 倍。在这个区域，内皮细胞会经历 0.6-12 Pa 范围内的高 WSS 值。据报道，暴露于该范围内 WSS 的内皮细胞会表达 VEGF。此外，我们还证明了刚性更强的癌细胞会在血管内皮上产生更高的 WSS。在直径<16 μm 的毛细血管中，观察到细胞刚性对其局部微环境的强烈影响。WSS 诱导的内皮 VEGF 表达代表了癌细胞在微血管中黏附和转移的一个重要潜在机制。这项工作是理解驱动内皮细胞表达 VEGF 的机制并确定内皮细胞在微血管中降解糖萼的潜在机制的重要的第一步。鉴定与癌细胞-内皮细胞相互作用早期阶段相关的血管生成因子，并了解其调控机制，将有助于：首先，开发应用于诊断研究和治疗干预的抗血管生成策略；其次，准确预测不同类型的癌细胞最有可能在微血管中黏附的位置；最后，建立准确的标准，预测哪些癌症更容易转移。
