Open AccessFunctional and therapeutic relevance of hepatocyte growth factor/c‐MET signaling in synovial sarcoma
Author(s) -
Imura Yoshinori,
Nakai Takaaki,
Yamada Shutaro,
Outani Hidetatsu,
Takenaka Satoshi,
Hamada Kenichiro,
Araki Nobuhito,
Itoh Kazuyuki,
Yoshikawa Hideki,
Naka Norifumi
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13092
Subject(s) - hepatocyte growth factor , c met , autocrine signalling , synovial sarcoma , cancer research , protein kinase b , signal transduction , biology , paracrine signalling , apoptosis , microbiology and biotechnology , sarcoma , medicine , receptor , pathology , biochemistry
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.