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Hepatic Stellate Cells and Hepatocarcinogenesis.

ABSTRACT: Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

SUBMITTER: Barry AE

PROVIDER: S-EPMC7419619 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hepatic Stellate Cells and Hepatocarcinogenesis.

Barry Anna E AE Baldeosingh Rajkumar R Lamm Ryan R Patel Keyur K Zhang Kai K Dominguez Dana A DA Kirton Kayla J KJ Shah Ashesh P AP Dang Hien H

Frontiers in cell and developmental biology 20200805

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes a ...[more]

PMID: 32850829

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Project description:BackgroundLiver fibrosis and fibrosis-related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor-β (TGF-β) is a critical mediator of chronic liver fibrosis, targeting TGF-β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF-β/Smad7 signaling.MethodsA meta-analysis was performed to evaluate CKI intervention on viral hepatitis-induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl4 ) injection or methionine-choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF-β/Smad signaling and typical fibrosis-related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT-PCR, Western blotting, RNA-seq, immunofluorescence, and immunohistochemistry.ResultsBased on meta-analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF-βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI.ConclusionsOur results unveil the approach of CKI in rebalancing TGF-β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis.

Dataset Information

Hepatic Stellate Cells and Hepatocarcinogenesis.

Publications

Hepatic Stellate Cells and Hepatocarcinogenesis.

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