The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers
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The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers. / Bartneck, Matthias; Schrammen, Peter L; Möckel, Diana; Govaere, Olivier; Liepelt, Anke; Krenkel, Oliver; Ergen, Can; McCain, Misti Vanette; Eulberg, Dirk; Luedde, Tom; Trautwein, Christian; Kiessling, Fabian; Reeves, Helen; Lammers, Twan; Tacke, Frank.
In: CELL MOL GASTROENTER, Vol. 7, No. 2, 11.2018, p. 371-390.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers
AU - Bartneck, Matthias
AU - Schrammen, Peter L
AU - Möckel, Diana
AU - Govaere, Olivier
AU - Liepelt, Anke
AU - Krenkel, Oliver
AU - Ergen, Can
AU - McCain, Misti Vanette
AU - Eulberg, Dirk
AU - Luedde, Tom
AU - Trautwein, Christian
AU - Kiessling, Fabian
AU - Reeves, Helen
AU - Lammers, Twan
AU - Tacke, Frank
N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2018/11
Y1 - 2018/11
N2 - BACKGROUND & AIMS: Hepatocellular 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.METHODS: TAM 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.RESULTS: We 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.CONCLUSIONS: The HCC microenvironment in human patients 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.
AB - BACKGROUND & AIMS: Hepatocellular 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.METHODS: TAM 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.RESULTS: We 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.CONCLUSIONS: The HCC microenvironment in human patients 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.
KW - Aged
KW - Animals
KW - Carcinogenesis/pathology
KW - Carcinoma, Hepatocellular/blood supply
KW - Chemokine CCL2/antagonists & inhibitors
KW - Cohort Studies
KW - Disease Models, Animal
KW - Disease Progression
KW - Endothelial Cells/pathology
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Liver Cirrhosis/pathology
KW - Liver Neoplasms/blood supply
KW - Macrophages/pathology
KW - Male
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Myeloid Cells/metabolism
KW - Neovascularization, Pathologic/pathology
KW - Phenotype
KW - RNA, Messenger/genetics
KW - Receptors, CCR2/metabolism
KW - Tumor Burden
U2 - 10.1016/j.jcmgh.2018.10.007
DO - 10.1016/j.jcmgh.2018.10.007
M3 - SCORING: Journal article
C2 - 30704985
VL - 7
SP - 371
EP - 390
JO - CELL MOL GASTROENTER
JF - CELL MOL GASTROENTER
SN - 2352-345X
IS - 2
ER -
