Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and it accounts for 85–90% of all hepatic cancers
The natural history of liver cirrhosis is tightly linked with HCC: a chronic liver insult (viral hepatitis, alcohol intake or non-alcoholic steatohepatitis (NASH) among others), which is able to produce inflammation of the liver parenchyma, which in turn triggers the activation of hepatic stellate cells and portal myofibroblasts, resulting in progressive liver fibrosis and, in liver cirrhosis [1]
These findings suggested that hepatic steatosis progresses by factors other than anabolic synthesis such as inhibition of autophagy and lysosome dysfunction [38]
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and it accounts for 85–90% of all hepatic cancers. The natural history of liver cirrhosis is tightly linked with HCC: a chronic liver insult (viral hepatitis, alcohol intake or non-alcoholic steatohepatitis (NASH) among others), which is able to produce inflammation of the liver parenchyma, which in turn triggers the activation of hepatic stellate cells and portal myofibroblasts, resulting in progressive liver fibrosis and, in liver cirrhosis [1]. Both chronic inflammation and fibrosis are well known risk factors of cancer. Both mTORC1 and mTORC2 regulate each other by controlling the activity of ribosomal protein S6 kinase (S6K) and AKT respectively, the extent of these mechanisms is not completely understood [21]
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