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

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 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.

Macrophages significantly enhance wound healing in a vascularized skin model

“…43 The angiogenic remodeling correlated with macrophage activation and was blocked by inhibiting cytokines for macrophage recruitment. Macrophages activation and the consequences on angiogenesis were described by Bartneck et al 44 recently. Activated macrophages secrete growth factors such as bFGF, TGF-α, IGF-I, PDGF, VEGF, TGF-β, and cytokines such as IL-1, IL-6, IL-8, and TNF-α, which promote matrix remodeling and modulate the migration and proliferation of endothelial cells.…”

Liver Macrophages: Old Dogmas and New Insights

“…(60) Additionally, cell sorting from mice subjected to a combined fibrosis-cancer model induced by diethylnitrosamine followed by repetitive CCl 4 injections revealed distinct coexisting MoMF populations with specific gene expression patterns, suggesting inflammatory capacity (immature myeloid infiltrate), angiogenic and fibrogenic activity (classical tumorassociated macrophages), or immune-suppressive functions (myeloid-derived suppressor cells). (86) While KCs are stationary and crucial for initiating inflammation, drastic changes occur in the MoMF compartment following injury. MoMFs have been shown to be recruited to the injury site just a few hours after acute injury (40,53,87) and account for the majority of hepatic macrophages in models of chronic liver injury.…”

“…As such, CCL2 expression has a prognostic value in patients with hepatocellular carcinoma, and CCR2 blockade has been shown to inhibit cancer growth by favoring an antitumoral immune response (136) and inhibiting angiogenesis. (86) Recently, CD163, a macrophage-specific marker with anti-inflammatory functions, has been used to evidence the presence of tumor-associated macrophages in cholangiocarcinoma. The authors concluded that CD163 + macrophage number correlated with cholangiocarcinoma stage.…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…The drug is a Spiegelmer® ( l ‐isomers of RNA oligonucleotides)‐based therapeutic agent that interacts specifically with MCP‐1 and inhibits its activity . Very recently, the drug showed preclinical success in the treatment of liver cancer . Bindarit is a small‐molecule inhibitor of MCP‐1 that has completed phase II clinical trials for the treatment of diabetic nephropathy.…”