Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma
- 1 May 2007
- journal article
- Published by Elsevier BV in Journal of Hepatology
- Vol. 46 (5), 840-848
- https://doi.org/10.1016/j.jhep.2006.11.021
Abstract
Hepatocellular carcinoma (HCC) is amenable to only few treatments. Inhibitors of the kinase mTOR are a new class of immunosuppressors already in use after liver transplantation. Their antiproliferative and antiangiogenic properties suggest that these drugs could be considered to treat HCC. We investigated the antitumoral effects of mTOR inhibition in a HCC model. Hepatoma cells were implanted into livers of syngeneic rats. Animals were treated with the mTOR inhibitor sirolimus for 4 weeks. Tumor growth was monitored by MR imaging. Antiangiogenic effects were assessed in vivo by microvessel density and corrosion casts and in vitro by cell proliferation, tube formation and aortic ring assays. Treated rats had significantly longer survival and developed smaller tumors, fewer extrahepatic metastases and less ascites than controls. Sirolimus decreased intratumoral microvessel density resulting in extensive necrosis. Endothelial cell proliferation was inhibited at lower drug concentrations than hepatoma cells. Tube formation and vascular sprouting of aortic rings were significantly impaired by mTOR inhibition. Casts revealed that in tumors treated with sirolimus vascular sprouting was absent, whereas intussusception was observed. mTOR inhibition significantly reduces HCC growth and improves survival primarily via antiangiogenic effects. Inhibitors of mTOR may have a role in HCC treatment.Keywords
This publication has 29 references indexed in Scilit:
- Treatment of hepatocellular carcinomaCurrent Treatment Options in Gastroenterology, 2004
- Angiogenesis and hepatocellular carcinomaJournal of Hepatology, 2004
- Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progressionOncogene, 2004
- mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4EMolecular and Cellular Biology, 2004
- The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An UpdateAnnals of Internal Medicine, 2003
- Rapamycins: mechanism of action and cellular resistance.Cancer Biology & Therapy, 2003
- Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factorNature Medicine, 2002
- Estimating the world cancer burden: Globocan 2000International Journal of Cancer, 2001
- Serum Vascular Endothelial Growth Factor Predicts Venous Invasion in Hepatocellular Carcinoma : A Prospective StudyAnnals of Surgery, 2001
- Microvessel density of hepatocellular carcinoma: its relationship with prognosisZeitschrift für Krebsforschung und Klinische Onkologie, 1999