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Updated: Jul 5, 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
Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma
Hung Huynh1, Pierce K H Chow, Nallasivam Palanisamy
1Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, 11 Hospital Drive, Singapore 169610, Singapore. cmrhth@nccs.com.sg
Background/Aims:
Hepatocellular carcinoma is a leading cause of global cancer mortality, with standard chemotherapy being minimally effective in prolonging survival. We investigated if combined targeting of vascular endothelial growth factor protein and expression might affect hepatocellular carcinoma growth and angiogenesis.
Methods:
We treated patient-derived hepatocellular carcinoma xenografts with (i) bevacizumab; (ii) rapamycin; and (iii) bevacizumab plus rapamycin. Western blotting was employed to determine changes in the proteins. Apoptosis, vascular endothelial growth factor expression, microvessel density, and cell proliferation were analyzed by immunohistochemistry.
Results:
Hepatocellular carcinoma growth was inhibited by bevacizumab plus rapamycin treatment to a significantly greater degree than bevacizumab or rapamycin monotherapy. Reductions in tumor growth by bevacizumab plus rapamycin were associated with inhibition of downstream targets of the mammalian target-of-rapamycin pathway, reductions in vascular endothelial growth factor expression, and tumor microvessel density. Potentially additive effects of bevacizumab plus rapamycin included reductions in vascular endothelial growth factor expression, cyclin D1, and cyclin B1. In an intra-peritoneal model of hepatocellular carcinoma, bevacizumab plus rapamycin potently inhibited both intra-liver and intra-abdominal tumor growth, reduced ascites levels, and significantly prolonged mouse survival.
Conclusions:
Bevacizumab and rapamycin, which are both clinically approved drugs, may represent a novel molecularly-targeted combination treatment for hepatocellular carcinoma.
Insights
Bevacizumab and rapamycin combination therapy significantly inhibits hepatocellular carcinoma growth and angiogenesis. This novel treatment strategy shows promise for improving survival in hepatocellular carcinoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a major global cancer with limited chemotherapy efficacy.
- Targeting vascular endothelial growth factor (VEGF) and related pathways is a potential therapeutic strategy for HCC.
Purpose of the Study:
- To investigate the combined effect of bevacizumab and rapamycin on HCC growth and angiogenesis.
- To evaluate the molecular mechanisms underlying the combination therapy's efficacy.
Main Methods:
- Treatment of HCC xenografts with bevacizumab, rapamycin, or combination therapy.
- Analysis of protein changes via Western blotting.
- Assessment of apoptosis, VEGF expression, microvessel density, and proliferation using immunohistochemistry.
Main Results:
- Combination therapy significantly inhibited HCC tumor growth compared to monotherapy.
- Bevacizumab plus rapamycin reduced VEGF expression, microvessel density, and proliferation.
- The combination therapy prolonged survival and reduced ascites in an intra-peritoneal HCC model.
Conclusions:
- Bevacizumab and rapamycin combination therapy represents a novel molecularly-targeted approach for HCC.
- This combination may offer a new treatment option for patients with hepatocellular carcinoma.
