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

• Project/Area Number: 15K08943
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hokkaido 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: ¥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.

Research Products

• [Journal Article] Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma (2017)
  • 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
  • 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 carcinoma (2017)
  • Author(s): Osamu Maehara, Goki Suda et al.
  • Journal Title: Carcinogenesis Volume: 38 Issue: 11 Pages: 1073-1083
  • DOI: 10.1093/carcin/bgx095
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Acknowledgement Compliant