Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma

Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kunugasa, Seiji Naganuma, Kelly A. Whelan, Hiroshi NakagawaKoji Nakagawa, Hiroshi Takeda, Naoya Sakamoto

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Abstract

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.

Original languageEnglish
Article numberbgx095
Pages (from-to)1073-1083
Number of pages11
JournalCarcinogenesis
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Maehara, O., Suda, G., Natsuizaka, M., Ohnishi, S., Komatsu, Y., Sato, F., Nakai, M., Sho, T., Morikawa, K., Ogawa, K., Shimazaki, T., Kimura, M., Asano, A., Fujimoto, Y., Ohashi, S., Kagawa, S., Kunugasa, H., Naganuma, S., Whelan, K. A., ... Sakamoto, N. (2017). Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma. Carcinogenesis, 38(11), 1073-1083. [bgx095]. https://doi.org/10.1093/carcin/bgx095