Journal
CLINICAL SCIENCE
Volume 126, Issue 11-12, Pages 775-784Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20130081
Keywords
angiogenesis; everolimus; hepatic stellate cell; hepatocellular carcinoma; mammalian target of rapamycin (mTOR)
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Funding
- Swiss Science Foundation (INDO-SWISS GRANT) [123456, INT/SWISS/P-30/2009]
- Department of Science and Technology (Government of India) under the lndo-Swiss Joint Research Program (ISJRP), Oncosuisse [02541-02-2010]
- International Union of Biochemistry and Molecular Biology (IUBMB) via a Wood-Whelan Research Fellowship Award
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Progression of liver fibrosis to HCC (hepatocellular carcinoma) is a very complex process which involves several pathological phenomena, including hepatic stellate cell activation, inflammation, fibrosis and angiogenesis. Therefore inhibiting multiple pathological processes using a single drug can be an effective choice to curb the progression of HCC. In the present study, we used the mTOR inhibitor everolimus to observe its effect on the in vitro activation of hepatic stellate cells and angiogenesis. The results of the present study demonstrated that everolimus treatment blocked the functions of the immortalized human activated hepatic stellate cell line LX-2 without affecting the viability and migration of primary human stellate cells. We also observed that treatment with everolimus (20 nM) inhibited collagen production by activated stellate cells, as well as cell contraction. Everolimus treatment was also able to attenuate the activation of primary stellate cells to their activated form. Angiogenesis studies showed that everolimus blocked angiogenesis in a rat aortic ring assay and inhibited the tube formation and migration of liver sinusoidal endothelial cells. Finally, everolinnus treatment reduced the load of tumoral myofibroblasts in a rat model of HCC. These data suggest that everolimus targets multiple mechanisms, making it a potent blocker of the progression of HCC from liver fibrosis.
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