Role of mTOR system and its relation with somatostatin and dopamine receptors on cell proliferation, hormone secretion and intracellular signalling in hepatocellular and cholangiocellular carcinomas.

Abstract

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are among the most lethal of human malignancies with s a very poor prognosis, with a <3% 5-years survival rate for untreated cancer. The actual therapies are limited to a little percentage of patients they are often diagnosed in advanced stages or even in metastatic conditions. In the last years, the idea of an “omics revolution” has given the basis to a new kind of therapies cancer, a molecular approach. In this work, we have focused our attention on mTOR pathway, its inhibitors and on their antiproliferative effects evaluating not only cell lines viability decrease after treatment with them, but also the molecular mechanism at basis of this phenomenon. In addition, our research project has investigated also somatostatin and dopamine receptor expression with the purpose to identify a molecular profile of this cancer, using four different cell lines and 23 Caucasian patients. So, stimulation of these receptors with the correspondent ligands has demostrated that their best therapeutical effect is observed with use of drugs with affinity for two different receptors, probably due to heterodimerization of somatostatin receptors. These data have been confirmed by different kinds of experiments (evaluating proliferation, hormone secretion and intracellular signalling) revealing an emergent aspect of HCC, its neuroendocrine fenotype. Our future purpose is to clarify better some molecular aspects that regulate heterodimerization and to define the intracellular pathways activated by these analogues. We, also are going to evaluate the effects of a potential combination between mTOR inhibitors and somatostatin analogues underlining a possible signalling interaction.