Abstract
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.
Highlights
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, and HCC is amongst the leading causes of cancer death globally
Inflammation and ballooning could already be observed at the early stage in the non-alcoholic steatohepatitis (NASH)-HCC model, the severity of which gradually increased over time (Figure 1E)
Hepatic macrophages are key players in tumor initiation and progression. They sustain a tumorpromoting pro-inflammatory microenvironment, and at the same time respond to tumor- and stromal cell-derived signals to actively facilitate HCC progression
Summary
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, and HCC is amongst the leading causes of cancer death globally. Because of the rising incidence of obesity, diabetes and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form, non-alcoholic steatohepatitis (NASH), are projected to become the leading cause of HCC [1]. Due to the increasing incidence of obesity and NAFLD, additional diet-based models have been developed to reliably reproduce the pathological changes observed in human disease. The streptozotocin (STZ) + high-fat or western diet model induces HCC on a background of diabetes, NASH and liver fibrosis. The observations that there were at least 4 nodules with an average tumor growth rate of 150% from 16 to 20 weeks of age, no visible metastasis and preserved liver function suggested that HCC induced in this model is equivalent to more advanced stages B to C of the Barcelona Clinic Liver Cancer staging system for patients [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
