Walking on the Molecular Pathway: m-TOR Inhibition in the Liver Transplant Setting

Abstract

Hepatocellular carcinoma (HCC) is a major problem worldwide, representing the fifth most common tumor among the general population (1). Several molecular pathways seem to be involved in HCC growth and progression, realizing an intricate mechanism of proliferative and angiogenetic stimulation and inhibiting apoptosis. The recent identification of these molecular pathways has improved our knowledge of HCC tumorigenesis and has setted up a more specific approach to HCC treatment. However, since non advanced HCC is one of the most common indications for liver transplantation, the recent novelties in pharmacologic inhibition of HCC growth mechanisms have opened new interesting opportunities in recipients' immunosuppressive treatment. M-TOR inhibitors belong to the group of rapamycine analogues, are used as second line immunosuppressive drugs and capable to inhibit one of the most active molecular pathways in HCC cells: the m-TOR pathway. In this review, we explain the mechanism and the molecular elements involved, up- and downstream, in m-TOR activation, providing an overview of the other features of HCC tumorigenesis too. Moreover, we describe the effects of m-TOR inhibition on HCC cells in vitro and in animal models, as well as on liver transplant recipients at risk of or with a manifest tumor recurrence and on de novo post-transplant malignancies. Finally, we discuss the possible efficacy of a proper combined therapy, well tolerated by patients and active against multiple molecular targets, to obtain a synergistic effect on the tumor mass with the greatest benefit for patients' survival and quality of life.