The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers.
Cell Mol Gastroenterol Hepatol
; 7(2): 371-390, 2019.
Article
in En
| MEDLINE
| ID: mdl-30704985
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Hepatocellular
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Receptors, CCR2
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Liver Cirrhosis
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Liver Neoplasms
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Macrophages
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Neovascularization, Pathologic
Type of study:
Etiology_studies
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Incidence_studies
/
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Aged
/
Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Cell Mol Gastroenterol Hepatol
Year:
2019
Document type:
Article