Analysis of in vivo niches and therapeutic targets for cancer stem cells based on the visualization mechanism

• Project/Area Number: 15K15491
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Tanaka Shinji 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420)
• Co-Investigator(Kenkyū-buntansha): 中山 恒 東京医科歯科大学, 難治疾患研究所, 准教授 (10451923) ; 藍原 有弘 東京医科歯科大学, 医学部附属病院, 非常勤講師 (90451939)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 癌 / 幹細胞 / 膵腫瘍 / 免疫チェックポイント / ゲノム編集 / 分子標的剤 / トランスレーショナルリサーチ / 癌抑制遺伝子 / エピゲノム / 制御性T細胞 / 発癌 / トランスジェニックマウス

Outline of Final Research Achievements

Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic molecules of pancreatic neuroendocrine tumor (pNET). In this study, we identified CD73 overexpressed in pNET CSCs. The CD73-inhibitor APCP significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumorigenicity of pNET CSCs. Immunohistochemical analysis of clinical samples demonstrated CD73 expression was significantly correlated with the tumor invasion.
In addition, our genome editing studies revealed that pNET can acquire CSC potentials with tumorigenicity by knockout of tumor suppressor gene X. We identified "Y" as one of the direct targets of tumor suppressor X. In clinical samples, significantly frequent recurrence was recognized in pNETs with low X and high Y expression.
Recently, CD73 was reported as a potential inducer of PD-1 immune checkpoint factor. As a result of our studies, CD73 and Y might be promising therapeutic targets for pNET.

Research Products

• [Journal Article] Acquired resistance with epigenetic alterations under long-term anti-angiogenic therapy for hepatocellular carcinoma. (2017)
  • Author(s): Ohata Y, Akiyama Y, Shimada S, Mogushi K, Nakao K, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Molecular Cancer Therapeutics Volume: in press Issue: 6 Pages: 1155-1165
  • DOI: 10.1158/1535-7163.mct-16-0728
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ARID2 modulates DNA damage response in human hepatocellular carcinoma cells. (2017)
  • Author(s): Oba A, Shimada S, Akiyama Y, Nishikawaji T, Mogushi K, Ito H, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Asahara H, Kaida A, Miura M, Tanabe M, Tanaka S.
  • Journal Title: Journal of Hepatology Volume: in press Issue: 5 Pages: 942-951
  • DOI: 10.1016/j.jhep.2016.12.026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular pathogenesis and targeted therapy of pancreatic cancer. (2016)
  • Author(s): Tanaka S.
  • Journal Title: Annals of Surgical Oncology Volume: 23 Issue: S2 Pages: 197-205
  • DOI: 10.1245/s10434-015-4463-x
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. (2016)
  • Author(s): Katsuta, E., Tanaka, S., Mogushi, K., Shimada, S., Akiyama, Y., Aihara, A., Matsumura, S., Mitsunori, Y., Ban, D., Ochiai, T., Kudo, A., Fukamachi, H., Tanaka, H., Nakayama, K., Arii, S., Tanabe, M.
  • Journal Title: Int. J. Oncol. Volume: 48 Issue: 2 Pages: 657-669
  • DOI: 10.3892/ijo.2015.3299
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy controls centrosome number by degrading Cep63. (2016)
  • Author(s): Watanabe Y, Honda S, Konishi A, Satoko Arakawa S, Murohashi M, Yamaguchi H, Torii S, Tanabe M, Tanaka S, Warabi E, Shimizu S.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13508-13508
  • DOI: 10.1038/ncomms13508
  • NAID: 120007129257
  • Peer Reviewed / Open Access
• [Journal Article] Cancer stem-like properties in colorectal cancer cells with low proteasome activity. (2016)
  • Author(s): Munakata K, Uemura M, Tanaka S, Kawai K, Kitahara T, Miyo M, Kano Y, Nishikawa S, Fukusumi T, Takahashi Y, Hata T, Nishimura J, Takemasa I, Mizushima T, Ikenaga M, Kato T, Murata K, Carethers JM, Yamamoto H, Doki Y, Mori M.
  • Journal Title: Clinical Cancer Research Volume: 22 Issue: 21 Pages: 5277-5286
  • DOI: 10.1158/1078-0432.ccr-15-1945
  • Peer Reviewed
• [Journal Article] Proteasome activity is required for the initiation of precancerous pancreatic lesions. (2016)
  • Author(s): Furuyama T, Tanaka S, Shimada S, Akiyama Y, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Fukamachi H, Arii S, Kawaguchi Y, Tanabe M.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27044-27044
  • DOI: 10.1038/srep27044
  • NAID: 120006775931
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis. (2016)
  • Author(s): Ito H, Tanaka S, Akiyama Y, Shimada S, Adikrisna R, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Yamaoka S, Tanabe M.
  • Journal Title: Plos One Volume: - Issue: 1 Pages: e0146564-e0146564
  • DOI: 10.1371/journal.pone.0146564
  • Peer Reviewed / Open Access
• [Journal Article] CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. (2016)
  • Author(s): Katsuta E, Tanaka S, Mogushi K, Shimada S, Akiyama Y, Aihara A, Matsumura S, Mitsunori Y, Ban D, Ochiai T, Kudo A, Fukamachi H, Tanaka H, Nakayama K, Arii S, Tanabe M.
  • Journal Title: International Journal of Oncology Volume: 48 Issue: 9 Pages: 657-69
  • DOI: 10.1007/s00535-015-1159-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cancer stem cells as therapeutic targets of hepato-biliary-pancreatic cancers. (2015)
  • Author(s): Tanaka S.
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: in press Issue: 7 Pages: 531-537
  • DOI: 10.1002/jhbp.248
  • Peer Reviewed
• [Journal Article] A novel Aurora/VEGFR dual kinase inhibitor as treatment for hepatocellular carcinoma. (2015)
  • Author(s): Nakao K, Tanaka S, Miura T, Sato K, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Tanabe M.
  • Journal Title: Cancer Science Volume: 106(8) Issue: 8 Pages: 1016-1022
  • DOI: 10.1111/cas.12701
  • Peer Reviewed / Open Access
• [Journal Article] A novel therapeutic combination targeting sequentially Aurora B and Bcl-xL in hepatocellular carcinoma. (2015)
  • Author(s): Matsunaga H, Tanaka S, Aihara A, Ogawa K, Matsumura S, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Arii S, Tanabe M.
  • Journal Title: Annals of Surgical Oncology Volume: 22(9) Issue: 9 Pages: 1016-1022
  • DOI: 10.1245/s10434-014-4292-3
  • Peer Reviewed
• [Presentation] シンポジウム：臨床検体のゲノム解析に基づいた遺伝子改変およびゲノム編集技術の臨床応用 (2016)
  • Author(s): 田中真二、島田周、古山貴基、大庭篤志、茂櫛薫、秋山好光、水野裕貴、小川康介、深町博史、伊藤浩光、光法雄介、松村聡、藍原有弘、伴大輔、落合高徳、工藤篤、川口義弥、田邉稔
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪府、大阪市）
• [Presentation] シンポジウム：肝癌の幹細胞性解析とゲノム編集技術を用いた治療応用 (2016)
  • Author(s): 田中真二、藍原有弘、田邉稔
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
• [Presentation] シンポジウム：肝癌の幹細胞性解析とゲノム編集技術を用いた治療応用 (2016)
  • Author(s): 田中真二、佐藤公太、田邉稔
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県、幕張市）
• [Presentation] シンポジウム：肝胆膵がん個別化分類に基づいた癌幹細胞の治療抵抗性機序の解明と治療展開 (2016)
  • Author(s): 田中真二、伊藤浩光、古山貴基、藍原有弘、松村聡、光法雄介、伴大輔、落合高徳、工藤篤、田邊稔
  • Organizer: 第72回日本消化器外科学会総会
  • Place of Presentation: あわぎんホール（徳島県、徳島市）
• [Presentation] 癌幹細胞のエピジェネティック変化と転移性および治療抵抗性獲得機序 (2016)
  • Author(s): 田中真二、島田周、秋山好光
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
• [Presentation] ワークショップ：肝癌分子標的薬の生体内感受性バイオマーカー探索と臨床展開 (2016)
  • Author(s): 田中真二、大畠慶映、田邉稔
  • Organizer: 第14回日本消化器外科学会大会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県、神戸市）
• [Presentation] Symposium: Surgical oncology for identification of novel molecular targets in refractory cancers. (2015)
  • Author(s): Tanaka S.
  • Organizer: The 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya
  • Year and Date: 2015-10-09
• [Presentation] Symposium: Molecular pathogenesis and targeted therapy for major vascular invasiveness of hepatocellular carcinoma. (2015)
  • Author(s): Tanaka S, Aihara A, Tanabe M.
  • Organizer: The 13th General Meeting of the Japanese Society of Gastroenterological Surgery
  • Place of Presentation: Tokyo
  • Year and Date: 2015-10-08
• [Presentation] シンポジウム：難治性消化器癌の幹細胞性解析を基盤とした標的治療の前臨床試験 (2015)
  • Author(s): 田中真二、島田周、伊藤浩光、古山隆貴、藍原有弘、松村聡、伴大輔、落合高徳、工藤篤、田邉稔.
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: 浜松
  • Year and Date: 2015-07-15
• [Presentation] シンポジウム：幹細胞特性の機能的解析に基づいた肝癌標的治療の前臨床試験 (2015)
  • Author(s): 田中真二、古山隆貴、田邉稔.
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] パネルディスカッション：高度脈管侵襲肝細胞癌に対する術後補助療法の意義と分子生物学的解析 (2015)
  • Author(s): 田中真二、伊藤浩光、茂櫛薫、小川康介、藍原有弘、松村聡、伴大輔、落合高徳、入江工、工藤篤、田中博、有井滋樹、田邉稔.
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-17
• [Book] Human Stem Cell Toxicity (ed. Sherley JL) (2016)
  • Author(s): Tanaka S.
  • Total Pages: 299
  • Publisher: Royal Society of Chemistry (London)
• [Book] Cancer stem cells as therapeutic targets. (Human Stem Cell Toxicity; ed. Sherley JL) (2016)
  • Author(s): Tanaka S.
  • Publisher: Royal Society of Chemistry
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/monc/index.html