Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma

Semela, David; Piguet, Anne-Christine; Kolev, Mirjam; Schmitter, Karin; Hlushchuk, Ruslan; Djonov, Valentin; Stoupis, Christoforos; Dufour, Jean-François (2007). Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. Journal of hepatology, 46(5), pp. 840-8. Amsterdam: Elsevier 10.1016/j.jhep.2006.11.021

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BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: mTOR inhibition significantly reduces HCC growth and improves survival primarily via antiangiogenic effects. Inhibitors of mTOR may have a role in HCC treatment.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Hlushchuk, Ruslan; Djonov, Valentin and Dufour, Jean-François

ISSN:

0168-8278

ISBN:

17321636

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:54

Last Modified:

04 May 2014 23:15

Publisher DOI:

10.1016/j.jhep.2006.11.021

PubMed ID:

17321636

Web of Science ID:

000246532000012

URI:

https://boris.unibe.ch/id/eprint/22925 (FactScience: 37750)

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