A multiscale in silico model of endothelial to mesenchymal transformation in a tumor microenvironment
A multiscale in silico model of endothelial to mesenchymal transformation in a tumor microenvironment
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DOI：
10.1016/j.jtbi.2019.08.012
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发表时间：
2019-11-07
影响因子：
2
通讯作者：
Murray, B. T.
中科院分区：
文献类型：
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作者：
Chowkwale, M.;Mahler, G. J.;Murray, B. T.
内皮细胞向间充质细胞转化（EndMT）是内皮细胞响应于机械生物学信号而获得间充质样表型的过程，其导致下层组织的重塑或修复。虽然最初与胚胎发育有关，但该过程已被证明发生在成人组织重塑中，包括伤口愈合，纤维化和癌症。为了了解EndMT在癌症进展和转移中的作用，我们提出了一个多尺度、三维的二氧化硅模型。该模型结合了组织水平的现象，如细胞外基质重塑，细胞水平的现象，如迁移和增殖，以及肿瘤微环境中的化学转运，以模拟癌症微环境的体外组织模型。该模型用于研究EndMT衍生的活化成纤维细胞（EDAF）的存在和不同基质硬度对肿瘤细胞迁移和增殖的影响。模拟准确地模拟了给定条件下肿瘤细胞的行为。EDAF的存在和/或基质硬度的增加导致肿瘤细胞活性的增加。该模型为进一步研究EDAF在肿瘤微环境中的细胞和亚细胞生理水平奠定了基础。(C)2019爱思唯尔有限公司版权所有。
Endothelial to mesenchymal transformation (EndMT) is a process in which endothelial cells gain a mesenchymal-like phenotype in response to mechanobiological signals that results in the remodeling or repair of underlying tissue. While initially associated with embryonic development, this process has since been shown to occur in adult tissue remodeling including wound healing, fibrosis, and cancer. In an attempt to understand the role of EndMT in cancer progression and metastasis, we present a multiscale, three-dimensional, in silica model. The model couples tissue level phenomena such as extracellular matrix remodeling, cellular level phenomena such as migration and proliferation, and chemical transport in the tumor microenvironment to mimic in vitro tissue models of the cancer microenvironment. The model is used to study the presence of EndMT-derived activated fibroblasts (EDAFs) and varying substrate stiffness on tumor cell migration and proliferation. The simulations accurately model the behavior of tumor cells under given conditions. The presence of EDAFs and/or an increase in substrate stiffness resulted in an increase in tumor cell activity. This model lays the foundation of further studies of EDAFs in a tumor microenvironment on a cellular and subcellular physiological level. (C) 2019 Elsevier Ltd. All rights reserved.