Characterization of the inflammatory microenvironment and hepatic macrophage subsets in experimental hepatocellular carcinoma models
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Helena Degroote1,2, Sander Lefere1,2, Astrid Vandierendonck1, Bart Vanderborght1,2, Tim Meese3, Filip Van Nieuwerburgh3, Xavier Verhelst1, Anja Geerts1, Hans Van Vlierberghe1 and Lindsey Devisscher2
1 Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
2 Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
3 Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
Keywords: hepatocellular carcinoma; macrophage subsets; tumor microenvironment; tumor associated macrophages; inflammation
Received: October 14, 2020 Accepted: February 15, 2021 Published: March 16, 2021
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. HCC typically develops on a background of chronic inflammation and fibrosis with tumor associated macrophages (TAMs) playing an important role in chronic inflammation-induced HCC and progression. However, the liver harbors unique macrophages, resident liver Kupffer cells (KCs) and monocyte-derived macrophages (Mo-Mφ), and their contribution to HCC and to the population of TAMs is incompletely known. Here, we characterized the tumor microenvironment and the proportion and transcriptional profile of hepatic macrophages (Mφ) in two commonly used HCC mouse models. A gradually increased expression of inflammatory, immune regulatory, fibrotic and cell proliferation pathways and markers was observed during diethylnitrosamine (DEN)- and non-alcoholic steatohepatitis (NASH)-induced HCC development. The transcriptional phenotypes of isolated hepatic Mφ subsets were clearly distinct and shifted during HCC development, with mixed pro-inflammatory and tumor-promoting expression profiles. There were marked differences between the models as well, with Mφ in NASH-HCC exhibiting a more immunomodulatory phenotype, in conjunction with an upregulation of lipid metabolism genes. Our data show that at least some infiltrated macrophages display expression of pro-tumoral markers, and that Kupffer cells are part of the population of TAMs and enhance tumor progression. These insights are useful to further unravel sequential pathogenic events during hepatocarcinogenesis and direct future development of new treatment strategies for HCC.
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