Development of cancer therapy targeting the metabolism activated by EpCAM in cancer stem cells.

• Project/Area Number: 24590389
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Keio University
• Principal Investigator: NAGANO Osamu 慶應義塾大学, 医学部, 講師 (30404346)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌幹細胞 / EpCAM / 糖代謝 / 代謝

Outline of Final Research Achievements

In this study, I analyzed the role of EpCAM, one of the major cancer stem cell markers, in the metabolism of cancer stem cell to develop new cancer therapy selectively targeting cancer stem cells. As a result, I found that EpCAM expression promotes the activation of pentose phosphate pathway and thereby promotes the reduction of oxidized glutathione. These results suggested that the combination therapy using the inhibitors for pentose phosphate pathway and glutathione synthesis might be effective to EpCAM-expressing cancer stem cells.

Research Products

• [Journal Article] CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma. (2014)
  • Author(s): Okabe H, Ishimoto T, Mima K, Nakagawa S, Hayashi H, Kuroki H, Imai K, Nitta H, Saito S, Hashimoto D, Chikamoto A, Ishiko T, Watanabe M, Nagano O, Beppu T, Saya H and Baba H
  • Journal Title: Br J Cancer Volume: 印刷中 Issue: 4 Pages: 958-66
  • DOI: 10.1038/bjc.2013.759
  • Peer Reviewed
• [Journal Article] Redox regulation in stem-like cancer cells by CD44 variant isoforms. (2013)
  • Author(s): Nagano O, Okazaki S, Saya H.
  • Journal Title: Oncogene Volume: 32 Issue: 44 Pages: 5191-5198
  • DOI: 10.1038/onc.2012.638
  • Peer Reviewed
• [Journal Article] CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. (2013)
  • Author(s): Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, Asakura K, Saya H, Hibi T
  • Journal Title: Br J Cancer Volume: 109 Issue: 2 Pages: 379-386
  • DOI: 10.1038/bjc.2013.314
  • Peer Reviewed
• [Journal Article] Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (2013)
  • Author(s): Wada T, Ishimoto T, Seishima R, Tsuchihashi K, Yoshikawa M, et al
  • Journal Title: Cancer Science Volume: 104 Issue: 10 Pages: 1323-9
  • DOI: 10.1111/cas.12236
  • Peer Reviewed
• [Journal Article] In vivo pH monitoring using boron doped diamond microelectrode and silver needles: Application to stomach disorder diagnosis. (2013)
  • Author(s): Fierro S, Seishima R, Nagano O, Saya H and Einaga Y
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 3257-3257
  • DOI: 10.1038/srep03257
  • Peer Reviewed
• [Journal Article] Lysyl oxidase is induced by cell density-mediated cell cycle suppression via RB-E2F1-HIF-1a axis. (2013)
  • Author(s): Goto TM, Arima Y, Nagano O, Saya H.
  • Journal Title: Cell Structure and Function Volume: 38 Pages: 9-14
  • Peer Reviewed
• [Journal Article] Gene expression profile of a newly established choriocarcinoma cell line, iC(3)-1, compared to existing choriocarcinoma cell lines and normal placenta. (2013)
  • Author(s): Kobayashi Y, Banno K, Shimizu T, Ueki A, Tsuji K, Masuda K, Kisu I, Nomura H, Tominaga E, Nagano O, Saya H, Aoki D.
  • Journal Title: Placenta Volume: 34 Issue: 2 Pages: 110-118
  • DOI: 10.1016/j.placenta.2012.11.003
  • Peer Reviewed
• [Journal Article] xCT Inhibition Depletes CD44v-Expressing Tumor Cells That Are Resistant to EGFR-Targeted Therapy in Head and Neck Squamous Cell Carcinoma. (2013)
  • Author(s): Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H, Nagano O.
  • Journal Title: Cancer Research Volume: 73 Pages: 1855-1866
  • Peer Reviewed
• [Journal Article] CD44s regulates the TGF-b-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. (2012)
  • Author(s): Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, Watanabe M, Beppu T, Tamada M, Nagano O, Saya H, Baba H
  • Journal Title: Cancer Research Volume: 72 Pages: 3414-3423
  • Peer Reviewed
• [Journal Article] Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. (2012)
  • Author(s): Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T,Mogushi K, Tanaka H, Osawa T, Kanki Y, et al
  • Journal Title: Nature Communications Volume: 6;3 Issue: 1 Pages: 883-883
  • DOI: 10.1038/ncomms1892
  • Peer Reviewed
• [Journal Article] In vivo assessment of cancerous tumors using boron doped diamond microelectrode. (2012)
  • Author(s): Fierro S, Yoshikawa M, Nagano O, Yoshimi K, Saya H, Einaga Y.
  • Journal Title: Scientific Reports Volume: 2 Issue: 1 Pages: 901-901
  • DOI: 10.1038/srep00901
  • Peer Reviewed
• [Journal Article] Reactive Oxygen Species-Induced Autophagic Degradation of Helicobacter pylori CagA Is Specifically Suppressed in Cancer Stem-like Cells (2012)
  • Author(s): Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, Nagano 0, Matsuzaki J, et al.
  • Journal Title: Cell Host & Microbe Volume: 12 Issue: 6 Pages: 764-777
  • DOI: 10.1016/j.chom.2012.10.014
  • Peer Reviewed
• [Presentation] がん幹細胞において活性化されるCD44v-xCTを介した抗酸化システムを標的とするがん治療戦略 (2014)
  • Author(s): 永野修
  • Organizer: 第37回日本分子生物学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-27
• [Presentation] 酸化ストレス回避機構を標的としたがん幹細胞治療戦略 (2014)
  • Author(s): 永野修
  • Organizer: 第30回日本DDS学会学術総会
  • Place of Presentation: 慶應義塾大学 薬学部 芝共立キャンパス（東京都港区）
  • Year and Date: 2014-07-31
• [Presentation] Redox regulation in stem-like cancer cells by CD44v (2014)
  • Author(s): 永野修
  • Organizer: 第73回日本がん学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-07-31
• [Presentation] Cancer treatment strategy targeting antioxidant system potentiated by CD44v-xCT in stem-like cancer cells. (2014)
  • Author(s): 永野修
  • Organizer: 第33回 札幌国際がんシンポジウム
  • Place of Presentation: ロイトン札幌(北海道札幌市)
  • Year and Date: 2014-06-28
  • Invited
• [Presentation] 酸化ストレス回避機構を標的とした癌幹細胞治療戦略
  • Author(s): 永野 修
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都国際会館
• [Presentation] Redox regulation in stem-like cancer cells by CD44v
  • Author(s): 永野 修
  • Organizer: 第11回日本臨床腫瘍学会
  • Place of Presentation: 東北大学百周年記念会館
• [Presentation] Redox regulation in stem-like cancer cells by CD44v
  • Author(s): 永野 修、佐谷秀行
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] The functional role of CD44 variant in cancer metastasis
  • Author(s): 永野 修
  • Organizer: 日本臨床口腔病理学会
  • Place of Presentation: 文京区
  • Invited
• [Presentation] CD44バリアントアイソフォームを介した腫瘍形成および癌転移機構の解明
  • Author(s): 永野 修
  • Organizer: 日本放射線影響学会
  • Place of Presentation: 仙台
  • Invited
• [Remarks] 慶應義塾大学医学部・先端医科学研究所・遺伝子制御部門
  • URL: http://www.genereg.jp/
• [Remarks] 慶應義塾大学 医学部 先端医科学研究所 遺伝子制御部門
  • URL: http://www.genereg.jp/
• [Remarks] 慶應義塾大学 医学部 先端医科学研究所 遺伝子制御部門
  • URL: http://genereg.jp/index.html