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FGFR inhibitors eliminate cancer stem-like cells in esophageal squamous cell carcinoma

Research Project

Project/Area Number 15K08943
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionHokkaido University

Principal Investigator

Natsuizaka Mitsuteru  北海道大学, 医学研究院, 客員研究員 (80642446)

Research Collaborator MAEHARA Osamu  北海道大学, 生命科学院, 大学院生
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords食道扁平上皮癌 / 癌幹細胞 / CD44 / EMT / FGFR阻害剤 / MEK阻害剤 / FGF
Outline of Final Research Achievements

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 be cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. 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 sharply diminishes CSCs via induction of mesenchymal-epithelial transition (MET). Further experiments revealed that Mek/Erk pathway is crucial for FGF-2-mediated CSC regulation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (10 results)

All 2017 2016 2015

All Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results)

  • [Journal Article] Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma2017

    • Author(s)
      Natsuizaka M、Whelan KA、Kagawa S、Tanaka K、Giroux V、Chandramouleeswaran PM、Long A、Sahu V、Darling DS、Que J、Yang Y、Katz JP、Wileyto E、Basu、Kita Y、Natsugoe S、Naganuma S、Klein-Szanto AJ、Diehl JA、Bass AJ、Wong Kwok-Kin、Rustgi AK、Nakagawa H
    • Journal Title

      Nat Commun

      Volume: 8 Issue: 1 Pages: 1758-1758

    • DOI

      10.1038/s41467-017-01500-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma2017

    • Author(s)
      Osamu Maehara, Goki Suda et al.
    • Journal Title

      Carcinogenesis

      Volume: 38 Issue: 11 Pages: 1073-1083

    • DOI

      10.1093/carcin/bgx095

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells.2017

    • Author(s)
      Yoshioka M, Ohashi S, Ida T, Nakai Y, Kikuchi O, Amanuma Y, Matsubara J, Yamada A, Miyamoto S, Natsuizaka M, Nakagawa H, Chiba T, Seno H, Muto M.
    • Journal Title

      J Exp Clin Cancer Res.

      Volume: 36 Issue: 1 Pages: 101-101

    • DOI

      10.1186/s13046-017-0572-7

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fluorescent imaging of superficial head and neck squamous cell carcinoma using a γ-glutamyltranspeptidase-activated targeting agent: a pilot study.2016

    • Author(s)
      Mizushima T, Ohnishi S, Shimizu Y, Hatanaka Y, Hatanaka KC, Hosono H, Kubota Y, Natsuizaka M, Kamiya M, Ono S, Homma A, Kato M, Sakamoto N, Urano Y
    • Journal Title

      BMC Cancer

      Volume: 16 Issue: 1 Pages: 411-411

    • DOI

      10.1186/s12885-016-2421-z

    • NAID

      120005773989

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma2016

    • Author(s)
      Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
    • Journal Title

      J Clin Pathol

      Volume: in press Issue: 7 Pages: 593-599

    • DOI

      10.1136/jclinpath-2015-203115

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection.2016

    • Author(s)
      Tsukuda Y, Suda G, Tsunematsu S, Ito J, Sato F, Terashita K, Nakai M, Sho T, Maehara O, Shimazaki T, Kimura M, Morikawa K, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Sakamoto N
    • Journal Title

      J Med Virol

      Volume: 89 Issue: 5 Pages: 857-866

    • DOI

      10.1002/jmv.24692

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C.2016

    • Author(s)
      Suda G, Kudo M, Nagasaka A, Furuya K, Yamamoto Y, Kobayashi T, Shinada K, Tateyama M, Konno J, Tsukuda Y, Yamasaki K, Kimura M, Umemura M, Izumi T, Tsunematsu S, Sato F, Terashita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N
    • Journal Title

      J Gastroenterol Hepatol

      Volume: EPub Issue: 7 Pages: 733-740

    • DOI

      10.1007/s00535-016-1162-8

    • NAID

      120006313426

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats.2015

    • Author(s)
      Onishi R, Ohnishi S, Higashi R, Watari M, Yamahara K, Okubo N, Nakagawa K, Katsurada T, Suda G, Natsuizaka M, Takeda H, Sakamoto N.
    • Journal Title

      Cell Transplant

      Volume: 24 Issue: 12 Pages: 26012614-26012614

    • DOI

      10.3727/096368915x687570

    • NAID

      120005690898

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition.2015

    • Author(s)
      Sato F, Kubota Y, Natsuizaka M, Maehara O, Hatanaka Y, Marukawa K, Terashita K, Suda G, Ohnishi S, Shimizu Y, Komatsu Y, Ohashi S, Kagawa S, Kinugasa H, Whelan KA, Nakagawa H, Sakamoto N.
    • Journal Title

      Cancer Biol Ther

      Volume: 16 Issue: 6 Pages: 933940-933940

    • DOI

      10.1080/15384047.2015.1040959

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma.2015

    • Author(s)
      Maehara O, Sato F, Natsuizaka M, Asano A, Kubota Y, Itoh J, Tsunematsu S, Terashita K, Tsukuda Y, Nakai M, Sho T, Suda G, Morikawa K, Ogawa K, Chuma M, Nakagawa K, Ohnishi S, Komatsu Y, Whelan KA, Nakagawa H, Takeda H, Sakamoto N.
    • Journal Title

      Cancer Biol Ther

      Volume: 16 Issue: 10 Pages: 14531461-14531461

    • DOI

      10.1080/15384047.2015.1070992

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant

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Published: 2015-04-16   Modified: 2019-03-29  

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