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The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers

Lookup NU author(s): Dr Olivier Govaere, Misti McCain

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Background & AimsHepatocellular carcinoma (HCC) typically arises in fibrotic or cirrhotic livers, which are characterized by pathogenic angiogenesis. Myeloid immune cells, specifically tumor-associated macrophages (TAMs), may represent potential novel therapeutic targets in HCC, complementing current ablative or immune therapies. However, the detailed functions of TAM subsets in hepatocarcinogenesis have remained obscure.MethodsTAM subsets were analyzed in-depth in human HCC samples and a combined fibrosis–HCC mouse model, established by i.p. injection with diethylnitrosamine after birth and repetitive carbon tetrachloride (CCl4) treatment for 16 weeks. Based on comprehensively phenotyping TAM subsets (fluorescence-activated cell sorter, transcriptomics) in mice, the function of CCR2+ TAM was assessed by a pharmacologic chemokine inhibitor. Angiogenesis was evaluated by contrast-enhanced micro–computed tomography and histology.ResultsWe show that human CCR2+ TAM accumulate at the highly vascularized HCC border and express the inflammatory marker S100A9, whereas CD163+ immune-suppressive TAM accrue in the HCC center. In the fibrosis–cancer mouse model, we identified 3 major hepatic myeloid cell populations with distinct messenger RNA profiles, of which CCR2+ TAM particularly showed activated inflammatory and angiogenic pathways. Inhibiting CCR2+ TAM infiltration using a pharmacologic chemokine CCL2 antagonist in the fibrosis–HCC model significantly reduced pathogenic vascularization and hepatic blood volume, alongside attenuated tumor volume.ConclusionsThe HCC microenvironment in human beings and mice is characterized by functionally distinct macrophage populations, of which the CCR2+ inflammatory TAM subset has pro-angiogenic properties. Understanding the functional differentiation of myeloid cell subsets in chronically inflamed liver may provide novel opportunities for modulating hepatic macrophages to inhibit tumor-promoting pathogenic angiogenesis.


Publication metadata

Author(s): Bartneck M, Schrammen P, Mockel D, Govaere O, Liepelt A, Krenkel O, Ergen C, McCain M, Eulberg D, Luedde T, Trautwein C, Kiessling F, Lammers T, Tacke F

Publication type: Article

Publication status: Published

Journal: Cellular and Molecular Gastroenterology and Hepatology

Year: 2019

Volume: 7

Issue: 2

Pages: 371-390

Online publication date: 18/10/2018

Acceptance date: 10/10/2018

Date deposited: 13/11/2018

ISSN (electronic): 2352-345X

Publisher: Elsevier

URL: https://doi.org/10.1016/j.jcmgh.2018.10.007

DOI: 10.1016/j.jcmgh.2018.10.007

Notes: Hepatocellular carcinoma typically arises in livers affected by long-standing chronic injury, persistent inflammation, and tissue scarring (fibrosis). We herein define in human samples and in a fibrosis–cancer mouse model a specialized population of infiltrating inflammatory cells, termed macrophages, that constitute the tumor environment and provide molecular signals for blood vessel formation to support tumor growth, termed angiogenesis. Inhibiting the macrophage infiltration of fibrotic livers by blocking chemotactic signals may provide a new therapeutic strategy to suppress pathogenic angiogenesis.


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