Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma.
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.
Semela
David
D
Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland.
Piguet
Anne-Christine
AC
Kolev
Mirjam
M
Schmitter
Karin
K
Hlushchuk
Ruslan
R
Djonov
Valentin
V
Stoupis
Christoforos
C
Dufour
Jean-François
JF
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
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus