title: Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma.
abstract: Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c-MET signaling in SS. Both HGF and c-MET were highly expressed in Yamato-SS cells, resulting in activation of c-MET and its downstream AKT and extracellular signal-regulated kinase signaling pathways, whereas c-MET was expressed but not activated in SYO-1 or HS-SY-II cells. c-MET-activated Yamato-SS cells showed higher anchorage-independent growth ability and less sensitivity to chemotherapeutic agents than did c-MET-inactivated SYO-1 or HS-SY-II cells. INC280, a selective c-MET inhibitor, inhibited growth of Yamato-SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c-MET and its downstream effectors in Yamato-SS cells. Co-expression of HGF and c-MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS. HGF/c-MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c-MET inhibitors.
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.|Musculoskeletal Oncology Service, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Yoshinori
authors: Y
authors: Imura
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Takaaki
authors: T
authors: Nakai
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Shutaro
authors: S
authors: Yamada
authors: Musculoskeletal Oncology Service, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Hidetatsu
authors: H
authors: Outani
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Satoshi
authors: S
authors: Takenaka
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Kenichiro
authors: K
authors: Hamada
authors: Musculoskeletal Oncology Service, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Nobuhito
authors: N
authors: Araki
authors: Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Kazuyuki
authors: K
authors: Itoh
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Hideki
authors: H
authors: Yoshikawa
authors: Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.|Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Norifumi
authors: N
authors: Naka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D051379:Mice; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: INC280; Yamato-SS; c-MET; hepatocyte growth factor; synovial sarcoma