Activated Hepatic Stellate Cells in Hepatocellular Carcinoma: Their Role as a Potential Target for Future Therapies

Geng

ACS Pharmacol. Transl. Sci.

2023

Oleanolic acid (OA), a common pentacyclic triterpenoid found in plants, has several therapeutic uses, including the treatment of hepatopathy disorders. However, due to OA's weak permeability and limited bioavailability, its therapeutic advantages are limited. Here, we showed that a short peptide known as p10 not only binds to OA but also rapidly enhances OA delivery into cultured hepatic stellate cells (HSCs), lowers their synthesis of fibrogenic proteins, and further reduces the HSC migration capacity. Our findings show that noncovalently conjugating short peptides to OA improves its pharmacological efficacy and permeability.

Section: ■ Discussionmentioning

confidence: 99%

Delivery of Oleanolic Acid with Improved Antifibrosis Efficacy by a Cell Penetrating Peptide P10

Geng

ACS Pharmacol. Transl. Sci.

2023

Section: Immune Escape Of Tumor Cellsmentioning

confidence: 99%

“…Macrophages and HSCs play an important role in tumor immune escape [160]. Both cell type are able to inhibit an effective cytotoxic T-cell response by expressing high levels of PD-L1 on their cell surface [77,107,[160][161][162][163]. Additionally, HSCs promote T-cell apoptosis and inhibit T-cell proliferation through the C3 pathway [164], and both macrophages and HSCs are able to induce the expansion of myeloid-derived suppressor cells (MDSCs) [165] and Th17 cells [107,160].…”

Section: Immune Escape Of Tumor Cellsmentioning

confidence: 99%

“…Both cell type are able to inhibit an effective cytotoxic T-cell response by expressing high levels of PD-L1 on their cell surface [77,107,[160][161][162][163]. Additionally, HSCs promote T-cell apoptosis and inhibit T-cell proliferation through the C3 pathway [164], and both macrophages and HSCs are able to induce the expansion of myeloid-derived suppressor cells (MDSCs) [165] and Th17 cells [107,160]. MDSCs promote hepatocarcinogenesis in a variety of ways including the recruitment of regulatory T cells via the secretion of IL-10 and TGF-β and inhibition of cytotoxic T cells by stimulating the expression of PD-L1 on tumor cells, thus mediating immune evasion [166,167].…”

Section: Immune Escape Of Tumor Cellsmentioning

confidence: 99%

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Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease

Son

Verschuren

Hanemaaijer

et al. 2023

Cancers

Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.

“…Quiescent HSCs are typically very sensitive to extracellular fibrotic stimuli that arise from tissue injury, hepatitis, or inflammation. Quiescent HSCs, which have an abundance of vitamin A in lipid droplets, are important for normal immune function (11). However, activated HSCs located at the site of an injury produce a temporary scar of the extracellular matrix (ECM).…”

Section: Hepatic Stellate Cells (Hscs)mentioning

confidence: 99%

Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models

Kim

Lee

Seo

2023

BMB Rep

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal.Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo.However, the information provided by an MCTS model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases. clinical utility of drugs that proved effective in vitro is low. Also, assays of liver function, including cell polarization, albumin synthesis, bile secretion, and urea synthesis, are better when they are performed in three-dimensional (3D) cell cultures that more accurately reflect the normal context of liver cells (7). Similarly, 3D cells provide a better model system for cancer drug discovery.The interactions between the tumor and the tumor microenvironment (TME) play a critical role in cell differentiation, tumorigenesis, metastasis, and the efficacy of drug therapies. Therefore it was important to develop a 3D TME platform to discover new therapeutics for liver cancer drug discovery. These platforms are complex and expensive to produce; however, the recently developed multicellular tumor spheroid (MCTS) models provide a new platform for highthroughput screening (HTS) of drugs to treat a variety of diseases, including cancers and infections.The development of 3D multicellular hepatic spheroid (MCHS) models has had a major impact on drug discovery and the identification of novel targets for the treatment of HCC and fibrosis. MCHS models should greatly increase the number of potential new drugs to treat HCC and reduce the time to drug discovery.In this review, we describe the influence of components of the TME on tumorigenesis, fibrogenesis, and chemoresistance in HCC, as well as advanced strategies that exploit 3D multicellular spheroid models to identify novel cancer targets and therapeutics.