Hudson, Shanice V., Miller, Hunter A., Mahlbacher, Grace E., Saforo, Douglas, Beverly, Levi J., Arteel, Gavin E., Frieboes, Hermann B. Computational/experimental evaluation of liver metastasis post hepatic injury: interactions with macrophages and transitional ECM. Scientific Reports volume 9, Article number: 15077 (2019)
ABSTRACT
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-α levels were 5× higher with M1 vs. M2 macrophages. Metastatic cell co-culture exhibited 10× higher TNF-α induction than with primary tumor cells. Although TGFβ1 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.
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