Related Experiment Video
Updated: Jun 25, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma
Hung Huynh1, Van Chanh Ngo1, Heng Nung Koong2
1Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Abstract:
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC.
Insights
Sorafenib effectively inhibits hepatocellular carcinoma (HCC) growth by targeting key signaling pathways. Combination therapy with mTOR inhibitors shows promise for enhanced anti-tumor activity in HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern.
- Growth, neovascularization, and metastasis in HCC are regulated by growth factor signaling pathways.
Purpose of the Study:
- To evaluate the in vivo anti-tumor efficacy of sorafenib tosylate in patient-derived HCC xenografts.
- To elucidate the molecular mechanisms underlying sorafenib's anti-tumor activity and resistance.
Main Methods:
- Treatment of four patient-derived HCC xenografts with sorafenib tosylate at 50 mg/kg and 100 mg/kg.
- Analysis of tumor growth, apoptosis, angiogenesis, and signaling pathway modulation (e.g., Raf/MEK/ERK, mTOR).
- Combination therapy studies with anti-HGF antibody and rapamycin in resistant xenografts.
Main Results:
- Sorafenib significantly inhibited tumor growth (85-96%) and induced apoptosis.
- Sorafenib suppressed angiogenesis and modulated key signaling proteins, including VEGFR, PDGFR, and components of the Raf/MEK/ERK pathway.
- Resistance in some xenografts was linked to increased HGF/c-met/mTOR signaling, which was overcome by combination therapy with rapamycin.
Conclusions:
- Sorafenib demonstrates potent in vivo anti-tumor activity in HCC xenografts.
- Combination therapy with mTOR inhibitors (like rapamycin) may overcome sorafenib resistance and enhance efficacy in HCC treatment.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway