Roa JC.1,2, Leal P.1, García P.2, Weber H.1, Sandoval A.1, Buchegger K.1, Tapia O.1, Grez M.3.
1Department of Pathology, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile; 2Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile; 3Institute for Biomedical Research Georg-Speyer-Haus, Frankfurt, Germany.
Introduction: Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor prognosis. Effective therapeutic strategies are urgently needed to improve the prognosis of GBC patients. Objective: To analyze the expression of mTOR/p70S6K signaling pathway in GBC and to evaluate the effect of mTOR inhibitors in in vitro and in vivo models of GBC. Methods: Expression of mTOR/p70S6K pathway components was examined by immunohistochemistry (primary tumors and chronic cholecystitis) and by Western blot (GBC cell lines). The in vitro effect of four mTOR inhibitors on cell viability and migration was assessed. Therapeutic effect of Rapamycin was evaluated in subcutaneous tumor models (NOD/ SCID mice). Treatment started when tumor had reached 100 mm3. Animals were divided and treated with vehicle and 10 mg/kg of Rapamycin, daily IP injection (5 days/week for 3 weeks). Mice were sacrificed 30 days after treatment and tumors were dissected and measured. Results: mTOR/ p70S6K pathway is frequently activated in GBC (> 60% of tumors showed high expression of phospho-mTOR and phospho-p70S6K, compared to CC). The treatment of cell lines with different mTOR inhibitors significantly reduced their viability and migration capacity (P < 0.05). In the subcutaneous tumor models, treatment with Rapamycin significantly reduced the weight and tumor volume compared with the control group (P < 0.001 for each comparison). Conclusion: mTOR/p70S6K signaling pathway is frequently activated in GBC tissues and cells lines, which suggest that this pathway could be a potential therapeutic target for the treatment of advanced GBC, using Rapamycin or other specific inhibitors. [FONDECYT 1090171/DIUFRO DI11-0039].