Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612768
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

Genetic deletion of Cxcr3 triggers HCC progression in mice by mediating accumulation of anti-inflammatory/pro-angiogenic tumor associated macrophages

Authors

  • E Brandt

    1   University Hospital of Aachen, Medical Department III, Aachen

  • P Fischer

    1   University Hospital of Aachen, Medical Department III, Aachen

  • T Wirtz

    1   University Hospital of Aachen, Medical Department III, Aachen

  • C Trautwein

    1   University Hospital of Aachen, Medical Department III, Aachen

  • H Sahin

    1   University Hospital of Aachen, Medical Department III, Aachen

  • M Berres

    1   University Hospital of Aachen, Medical Department III, Aachen
Further Information

Publication History

Publication Date:
03 January 2018 (online)

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    Background and aims:

    HCC progression is associated with neovascularization and infiltrating immune cells. The chemokine receptor CXCR3 is involved in these processes and plays an important role during liver injury and fibrogenesis in mice and human. Here we aimed to investigate the role of CXCR3 during HCC progression.

    Methods:

    A fibrosis-triggered cancer mouse model encompassing a single i.p. injection of N-Diethylnitrosamin (DEN, 14 d after birth) and weekly i.p. injections of low dose carbon tetrachloride (CCl4, week 4 – 26) was applied to Cxcr3-/- and wild-type (WT) mice. Tumor burden was assessed after 26 weeks and tissue was histologically analyzed for the marker Ki67, CD31, KDR, Cleaved Caspase 3. Leukocyte subpopulations were measured by flow cytometry and immunofluorescence staining (IF; CD68, F4/80) in tumor and surrounding tissue with specific focus on tumor associated macrophage (TAM)-related immune responses. In vitro, Cxcr3-/- and WT bone marrow culture-derived macrophages (BMM) and TAMs were characterized utilizing qRT-PCR, flow cytometry and TUNEL staining.

    Results:

    Treatment of Cxcr3 -/- mice with DEN/CCl4 led to an increased tumor burden (P< 0.01) compared to WT mice, which was strongly associated with a higher number of Ki67 tumor cells (P< 0.05) and enhanced CD31 microvessel density (P< 0.01). Moreover, IF showed an accumulation of CD68 macrophages (P < 0.01) associated with reduced number of apoptotic macrophages (Cleaved caspase 3 staining, P < 0.01) in tumor and surrounding tissue of Cxcr3 -/- mice, which could be further subcategorized to an anti-inflammatory Ly6Clow/MHCIIlow phenotype by flow cytometry analysis. In vitro analysis of WT and Cxcr3 -/- BMM and TAMs demonstrated that Cxcr3 deficiency fosters survival and expression of anti-inflammatory, pro-angiogenetic cytokines and hepatic growth factor (qPCR) in macrophages, which was also reflected by expression analysis in the mouse model.

    Conclusions:

    Our results define Cxcr3 as a regulator of HCC progression by governing macrophage survival and polarization as well as angiogenesis in mice. These data imply Cxcr3 and its ligands as new targets for HCC treatment modulating macrophage polarization and neovascularization.