title: Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kolev
authors.forename: Karin
authors.initials: K
authors.lastname: Schmitter
authors.forename: Ruslan
authors.initials: R
authors.lastname: Hlushchuk
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.forename: Christoforos
authors.initials: C
authors.lastname: Stoupis
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus