Deletion of MyD88 in non-parenchymal cells, but not in parenchymal cells attenuates the progression of hepatocellular carcinoma

CONTEXT AND OBJECTIVE: Nestin, a class VI intermediate filament protein, is highly expressed in the portal mesenchyme and sinusoidal endothelium of the human fetal liver, but scarcely expressed in adult portal vessel endothelium. During experimental liver regeneration, an increased number of nestin-positive parenchymal cells have been observed in the zone adjacent to the Hering canals. These parenchymal cells are regarded as hepatic stem cells or hepatoblasts, which may be involved in hepatocellular carcinogenesis. In the light of recent reports describing nestin-positive parenchymal cells in hepatocellular carcinoma, we aimed to use this tumor type as a positive control for immunohistochemical detection of nestin. DESIGN AND SETTING: Experimental study conducted at a university hospital. METHODS: Hepatocellular carcinoma sections from one case were analyzed for nestin expression by immunohistochemistry using confocal microscopy. RESULTS: Surprisingly, a conspicuous pattern resembling liver sinusoid-like cytoarchitecture was observed upon nestin staining of endothelial cells. CONCLUSIONS: This pattern has not been previously described. The preliminary results shown here suggest that nestin-positive endothelial cells are located in niches of immature or proliferative cells. Moreover, nestin expression in endothelial cells of hepatocellular carcinoma enhances the role of angiogenesis in this tumor type, although the prevalence of this immunohistopathological pattern remains to be determined. Finally, hepatocellular carcinoma is an effective positive control for nestin staining in fluorescent immunohistochemistry.

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TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms

Gut ◽

10.1136/gutjnl-2019-319227 ◽

2020 ◽

pp. gutjnl-2019-319227 ◽

Cited By ~ 1

Author(s):

Aitor Esparza-Baquer ◽

Ibone Labiano ◽

Omar Sharif ◽

Aloña Agirre-Lizaso ◽

Fiona Oakley ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Regeneration ◽

Protective Role ◽

Hepatocyte Proliferation ◽

Protective Mechanisms ◽

Liver Tumours ◽

Parenchymal Cells ◽

Antioxidant Diet ◽

The Impact

ObjectiveHepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis.DesignTREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted.ResultsTREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion.ConclusionTREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.

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Mechanisms of liver fibrosis and its role in liver cancer

Experimental Biology and Medicine ◽

10.1177/1535370219898141 ◽

2020 ◽

Vol 245 (2) ◽

pp. 96-108 ◽

Cited By ~ 4

Author(s):

Debanjan Dhar ◽

Jacopo Baglieri ◽

Tatiana Kisseleva ◽

David A Brenner

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Cell Types ◽

Cytokines And Chemokines ◽

Metabolic Remodeling ◽

Advanced Liver Fibrosis ◽

Parenchymal Cells ◽

Potential Therapeutic Intervention

Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma. Impact statement Advanced liver fibrosis results in cirrhosis, portal hypertension, and liver failure and often requires liver transplantation. Advanced liver fibrosis and cirrhosis are also major risk factors for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) play a pivotal role in the pathogenesis of liver fibrosis. In this review, we summarize the basic mechanisms that influence liver fibrosis development and how oxidative stress, mitochondrial dysfunction, and metabolic remodeling modulate HSC activation and indicate areas of potential therapeutic intervention.

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Deletion of MyD88 in non-parenchymal cells, but not in parenchymal cells attenuates the progression of hepatocellular carcinoma

Journal of Hepatology ◽

10.1016/s0168-8278(18)31593-9 ◽

2018 ◽

Vol 68 ◽

pp. S668

Author(s):

A. Mohs ◽

N. Hermanns ◽

T. Otto ◽

S.A.Y. Hassan ◽

A. de Bruin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Parenchymal Cells

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Immunocytochemical detection of hepatic carbohydrate metabolic enzymes: Improved resolution with polyethylene glycol embedding and visio-bond semithin sections

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100124367 ◽

1992 ◽

Vol 50 (1) ◽

pp. 792-793

Author(s):

Kuixiong Gao ◽

Randal E. Morris ◽

Bruce F. Giffin ◽

Robert R. Cardell

Keyword(s):

Polyethylene Glycol ◽

Glycogen Phosphorylase ◽

Phosphoenolpyruvate Carboxykinase ◽

Glycogen Synthase ◽

Metabolic Enzymes ◽

Silver Stain ◽

Accurate Localization ◽

Immunocytochemical Detection ◽

Semithin Sections ◽

Parenchymal Cells

Several enzymes are involved in the regulation of anabolic and catabolic pathways of carbohydrate metabolism in liver parenchymal cells. The lobular distribution of glycogen synthase (GS), phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP) was studied by immunocytochemistry using cryosections of normal fed and fasted rat liver. Since sections of tissue embedded in polyethylene glycol (PEG) show good morphological preservation and increased detectability for immunocytochemical localization of antigenic sites, and semithin sections of Visio-Bond (VB) embedded tissue provide higher resolution of cellular structure, we applied these techniques and immunogold-silver stain (IGSS) for a more accurate localization of hepatic carbohydrate metabolic enzymes.

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