Computational/experimental evaluation of liver metastasis post hepatic injury: interactions with macrophages and transitional ECM
Computational/experimental evaluation of liver metastasis post hepatic injury: interactions with macrophages and transitional ECM
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DOI：
10.1038/s41598-019-51249-y
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发表时间：
2019-10-21
影响因子：
4.6
通讯作者：
Frieboes, Hermann B.
中科院分区：
文献类型：
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作者：
Hudson, Shanice V.;Miller, Hunter A.;Frieboes, Hermann B.
损伤后肝细胞外基质(ECM)的亚临床变化与肿瘤相关的巨噬细胞微环境信号促进转移细胞种植之间的复杂相互作用仍然知之甚少。这项研究采用计算模型和实验相结合的方法来评估肝损伤后肿瘤的生长，重点是ECM重塑和与局部巨噬细胞的相互作用。实验测定ECM密度和巨噬细胞相关细胞因子水平。通过计算模型评估ECM重塑和巨噬细胞极化对肿瘤生长的影响。对于与巨噬细胞共培养的原代或转移细胞，M1巨噬细胞的肿瘤坏死因子-α水平是M2巨噬细胞的5倍。转移细胞共培养的肿瘤坏死因子-α的诱导率是原代肿瘤细胞的10倍。尽管转化生长因子β1在两种共培养体系中的诱导作用相似，但在M1存在的情况下，原代细胞的转化生长因子β1水平略高。与原发肿瘤相比，模拟转移性肿瘤表现出生长减慢，这是由于局部M1诱导的高度细胞毒性，即使在高度血管化的微环境中也是如此。实验分析结合计算模型可以深入了解细胞外基质重塑、巨噬细胞极化和肝肿瘤生长之间的相互作用。
The complex interactions between subclinical changes to hepatic extracellular matrix (ECM) in response to injury and tumor-associated macrophage microenvironmental cues facilitating metastatic cell seeding remain poorly understood. This study implements a combined computational modeling and experimental approach to evaluate tumor growth following hepatic injury, focusing on ECM remodeling and interactions with local macrophages. Experiments were performed to determine ECM density and macrophage-associated cytokine levels. Effects of ECM remodeling along with macrophage polarization on tumor growth were evaluated via computational modeling. For primary or metastatic cells in co-culture with macrophages, TNF-alpha levels were 5x higher with M1 vs. M2 macrophages. Metastatic cell co-culture exhibited 10x higher TNF-alpha induction than with primary tumor cells. Although TGF beta 1 induction was similar between both co-cultures, levels were slightly higher with primary cells in the presence of M1. Simulated metastatic tumors exhibited decreased growth compared to primary tumors, due to high local M1-induced cytotoxicity, even in a highly vascularized microenvironment. Experimental analysis combined with computational modeling may provide insight into interactions between ECM remodeling, macrophage polarization, and liver tumor growth.