title: Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma.
abstract: Antiangiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma; however, they finally relapse and progress, resulting in poor prognosis. We here establishedin vivodrug-tolerant subclones of human hepatocellular carcinoma cells by long-term treatment with VEGF receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tβ4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tβ4 in hepatocellular carcinoma cells could significantly enhance sphere-forming capacities and infiltrating phenotypesin vitro, and promote growth of tumors refractory to the VEGFR multikinase inhibitor sorafenibin vivoClinically, sorafenib failed to improve the progression-free survival in patients with Tβ4-high hepatocellular carcinoma, indicating that Tβ4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma.Mol Cancer Ther; 16(6); 1155-65. ©2017 AACR.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Ohata
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mitsunori
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. tanaka.monc@tmd.ac.jp.|Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D000077157:Sorafenib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006657:Histones; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib