TY - JOUR
T1 - Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma
AU - Maehara, Osamu
AU - Natsuizaka, Mitsuteru
AU - Ohnishi, S
AU - Komatsu, Yoshito
AU - Sato, Fumiyuki
AU - Nakai, Masato
AU - Sho, Takuya
AU - Morikawa, Kenichi
AU - Ogawa, K
AU - Shimazaki, Tomoe
AU - Kimura, Megumi
AU - Asano, Ayaka
AU - Fujimoto, Yoshiyuki
AU - Ohashi, Shinya
AU - Kagawa, Shingo
AU - Kinugasa, H.
AU - Naganuma, Seiji
AU - Whelan, Kelly A.
AU - Nakagawa, Hiroshi
AU - Nakagawa, Koji
AU - Takeda, Hiroshi
AU - Sakamoto, Naoya
N1 - Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
AB - In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
KW - Benzamides/pharmacology
KW - Carcinoma, Squamous Cell/metabolism
KW - Cell Line, Tumor
KW - Epithelial-Mesenchymal Transition/drug effects
KW - Esophageal Neoplasms/metabolism
KW - Esophageal Squamous Cell Carcinoma
KW - Extracellular Signal-Regulated MAP Kinases/metabolism
KW - Fibroblast Growth Factor 2/metabolism
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - MAP Kinase Signaling System/drug effects
KW - Neoplastic Stem Cells/drug effects
KW - Piperazines/pharmacology
KW - Pyrazoles/pharmacology
KW - Pyridones/pharmacology
KW - Pyrimidinones/pharmacology
KW - Receptors, Fibroblast Growth Factor/metabolism
KW - Signal Transduction/drug effects
UR - http://www.scopus.com/inward/record.url?scp=85032730342&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgx095
DO - 10.1093/carcin/bgx095
M3 - Article
C2 - 28927233
SN - 0143-3334
VL - 38
SP - 1073
EP - 1083
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
M1 - bgx095
ER -