Clinical—Liver, Pancreas, and Biliary TractPivotal Role of mTOR Signaling in Hepatocellular Carcinoma
Section snippets
Human Tissue Samples
A total of 351 human liver samples obtained either from liver resection or transplantation were analyzed in different sets (Figure 1). All of the samples were obtained from the HCC Genomic Consortium: Mount Sinai School of Medicine in New York (United States), Hospital Clinic in Barcelona (Spain), and Istituto Nazionale dei Tumori in Milan (Italy). After institutional review board approval and after patient written informed consent was obtained, tissue specimens were collected. First, we used
mTOR pathway gene expression alterations, DNA copy number changes, and mutation analysis of HCV-related HCC
We conducted an expression study using quantitative reverse-transcription PCR in 2 different human cohorts: exploratory (n = 77) and replication (n = 78) sets (Figure 2 and Supplementary Figure 1; see Supplementary material online at www.gastrojournal.org). Dysregulation of key growth regulatory genes including EGF, IGFBP3, and PTEN was evident in overt HCC. EGF was up-regulated, particularly in advanced HCC cases (P = .001), and the tumor suppressor IGFBP3 was down-regulated in early and
Discussion
Recent studies have identified PI3K/AKT/mTOR pathway as a major oncogenic cascade for targeting molecular therapies in cancer.25 MTOR signaling has been implicated in the initiation and progression of multiple tumors, such as leiomyosarcomas and gliomas.26 We show herein that mTOR pathway is activated in a subset of patients with early HCC. Activation of mTOR cascade resulted from ligand-dependent signals from EGF and IGF signaling, rather than from a mutation-dependent mechanism, because no
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The authors would like to honor the memory of their colleague and friend, Eric R. Lemmer, member of the Mount Sinai Liver Cancer Program and the Division of Liver Diseases. The authors also want to thank Dr Ron Prywes (Columbia University, NY) for providing the c-fos luciferase reporter. The authors thank Novartis Pharma for providing the drugs (AEE788 and RAD001 in the context of an MTA) used in this study.
The authors disclose the following: Supported by a grant from Fundación Pedro Barrié de la Maza, Asociación Española para el Estudio del Hígado, National Cancer Center, and an European Association for the Study of the Liver-Sheila Sherlock Fellowship (A.V.); by a grant from Instituto de Salud Carlos III (FIS-CM04/00044 to B.M.); by the Italian Association for Cancer Research and the Italian National Ministry of Health (V.M.); by a grant from Instituto Carlos III (ISCIII/FIS PI 05-0150 to J.B.); by Institució Catalana de Recerca i Estudis Avançats and grants from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), the Samuel Waxman Cancer Research Foundation, and the Spanish National Health Institute (SAF-2007-61898) (J.L.); and by grants from the National Institutes of Health (1RO1DK37340-23 to S.F.). Philippa Newell is a recipient of an American Liver Foundation Fellowship and Yujin Hoshida is a recipient of a Charlie A. King Trust fellowship. M. Meyerson is a consultant for Novartis.