Related Experiment Video
Updated: Aug 27, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Treatment Strategies and Mechanisms Associated with the Prevention of NASH-Associated HCC by a Toll-like Receptor 4
Suet-Ying Kwan1, Alyssa N Slayden1, Aubrey R Coronado1
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations.
Prevention Relevance:
Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC.
Insights
TAK-242, a Toll-like receptor 4 (TLR4) inhibitor, reduced hepatocellular carcinoma (HCC) development and adenoma progression in a mouse model of nonalcoholic steatohepatitis (NASH). This cancer prevention strategy involves decreased inflammation and improved mitochondrial function.
Area of Science:
- Hepatology
- Oncology
- Immunology
Background:
- Nonalcoholic steatohepatitis (NASH) is a growing cause of hepatocellular carcinoma (HCC), necessitating novel prevention strategies.
- Current therapeutic options for preventing HCC in NASH patients are limited, highlighting an unmet clinical need.
Purpose of the Study:
- To evaluate the cancer-preventive efficacy of TAK-242, a Toll-like receptor 4 (TLR4) inhibitor, in a mouse model of NASH-associated HCC.
- To investigate the cellular and molecular mechanisms underlying TAK-242's preventive effects.
Main Methods:
- Oral administration of TAK-242 (30 mg/kg) in a Pten-deficient mouse model of NASH-induced HCC.
- Assessment of tumor development, steatosis, liver enzymes, and gene expression profiles (RNA sequencing).
- Cell deconvolution analysis to determine changes in hepatic cell populations.
Main Results:
- TAK-242 treatment reduced tumor development and progression of small adenomas to HCC.
- Reduced macrovesicular steatosis and serum alanine aminotransferase levels were observed.
- TAK-242 modulated hepatic gene expression, decreased pro-inflammatory immune cells, and increased hepatocyte mitochondrial function.
Conclusions:
- TAK-242 demonstrates significant cancer preventive efficacy in a NASH-associated HCC mouse model.
- The mechanism involves reducing hepatic inflammation and enhancing mitochondrial function via TLR4 inhibition.
- These findings support further investigation of TAK-242 as a chemopreventive strategy for HCC in NASH patients.
More Related Videos
12:24A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
11:34A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
Published on: May 10, 2022
