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Di Matteo, Sabina; Nevi, Lorenzo; Overi, Diletta; Landolina, Nadine; Faccioli, Jessica; Giulitti, Federico; Napoletano, Chiara; Oddi, Andrea; Marziani, Augusto M; Costantini, Daniele; De Rose, Agostino M; Melandro, Fabio; Bragazzi, Maria C; Grazi, Gian Luca; Berloco, Pasquale B; Giuliante, Felice; Donato, Giuseppe; Moretta, Lorenzo; Carpino, Guido; Cardinale, Vincenzo; Gaudio, Eugenio; Alvaro, Domenico
Scientific reports, 01/2021, Volume: 11, Issue: 1Journal Article
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.
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