Computational/experimental evaluation of liver metastasis post hepatic injury: interactions with macrophages and transitional ECM

Shanice V. Hudson,Douglas Saforo,Gavin E. Arteel,Hermann B. Frieboes,Hunter A. Miller,Levi J. Beverly,Grace E. Mahlbacher

doi:10.1038/s41598-019-51249-y

Shanice V. Hudson, Douglas Saforo + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-51249-y

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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.

Highlights

Causes of liver disease include alcohol or toxicant exposure, obesity, and viral infection, among a host of cofactors
For tECM, M1 macrophages represented 68% and M2 were 4% of the total population. These results indicate that with the parameter set evaluated in this study, the macrophage polarization was mainly influenced by the tumor type
In addition to primary injuries, alcohol use contributes to a broad range of secondary pathologies, including notably an increased risk of oncogenesis in several organs

Summary

Introduction

Causes of liver disease include alcohol or toxicant exposure, obesity, and viral infection, among a host of cofactors. Www.nature.com/scientificreports perivascular TAMs present with a proinflammatory (‘classical’ M1) phenotype, stromal macrophages bordering hypoxic regions, exhibit a more anti-inflammatory (‘alternative’ M2) trophic phenotype[7] These M2-like TAMs release pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) in response to hypoxic cell signaling[8,9]. It remains poorly understood, to what extent the interactions of pro- and anti-inflammatory macrophage and ECM remodeling in the context of liver disease affect metastatic tumor growth and vascularization. We employ mathematical modeling to evaluate heterogeneous macrophage population interactions with tumor tissue[18], considering ECM from normal and injured liver, and perform experiments with a mouse model to represent the in vivo human condition

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