Establishment of human cancer microenvironment mouse model

• Project/Area Number: 16K08742
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kumamoto University
• Principal Investigator: OKADA SEIJI 熊本大学, エイズ学研究センター, 教授 (50282455)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 患者由来腫瘍移植モデル / 高度免疫不全マウス / 胆管細胞癌 / 悪性リンパ腫 / 固形癌 / がん微小環境 / 患者腫瘍移植マウスモデル / 原発性滲出性リンパ腫 / がん関連線維芽細胞 / 消化管間質腫瘍 / マウスモデル / 患者腫瘍組織移植モデル / 癌 / 動物

Outline of Final Research Achievements

We established cholangiocarcinoma lung and liver metastasis model, and showed that CD147 played important role for epithelial-mesenchymal transition and metastasis. We also established patient-derived xenograft (PDX) model of liver fluke derived cholangiocarcinoma. Five cell lines were established from 12 PDX samples.
We showed that autophagy is accelerated in Primary effusion lymphoma (PEL) and inhibition of autophagy induced apoptosis for PEL cells. We also showed that transcriptional factor, PU.1, is methylated in PEL cells and activation of PU.1 induced apoptosis for PEL cells. These results indicate that epigenetic regulation can be important target for treatment of PEL.

Academic Significance and Societal Importance of the Research Achievements

高度免疫不全マウスへの移植系を用いて難治性腫瘍であるヒト胆管細胞癌と悪性リンパ腫にヒト由来腫瘍細胞を移植する事でマウス生体内に「ヒトのがん微小環境」を構築した。本系は、ヒト腫瘍のAvatarとして難治性腫瘍の病態解析と治療薬開発に有用な系として期待される。また、悪性リンパ腫のエピジェネチックな制御機構の一端を解明し、新規治療法開発の可能性を示唆した。

Research Products

• [Int'l Joint Research] Khon Kaen 大学/Mahidol大学(タイ)
• [Int'l Joint Research] Khon Kaen大学/Mahidol大学/Burapha 大学(タイ)
• [Int'l Joint Research] ソウル国立大学(韓国)
• [Int'l Joint Research] コンケン大学医学部/マヒドン大学医学部シリラ病院/ブラパー大学薬学部・理学部(タイ)
• [Int'l Joint Research] ソウル国立大学薬学部(韓国)
• [Journal Article] Attenuation of CD47-SIRPα Signal in Cholangiocarcinoma Potentiates Tumor-Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis. (2018)
  • Author(s): Vaeteewoottacharn K, Kariya R, Pothipan P, Fujikawa S, Pairojkul C, Waraasawapati S, Kuwahara K, Wongkham C, Wongkham S, Okada S.
  • Journal Title: Translational Oncology Volume: 12 Issue: 2 Pages: 217-225
  • DOI: 10.1016/j.tranon.2018.10.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence. (2018)
  • Author(s): Laphanuwat P, Likasitwatanakul P, Sittithumcharee G, Thaphaengphan A, Chomanee N, Suppramote O, Ketaroonrut N, Charngkaew K, Lam EW, Okada S, Panich U, Sampattavanich S, Jirawatnotai S.
  • Journal Title: Journal of Cell Science Volume: 131
  • DOI: 10.1242/jcs.214726
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIV positivity may not have a negative impact on survival in Epstein-Barr virus-positive Hodgkin lymphoma: A Japanese nationwide retrospective survey. (2018)
  • Author(s): Yotsumoto M, Ito Y, Hagiwara S, Terui Y, Nagai H, Ota Y, Ajisawa A, Uehira T, Tanuma J, Ohyashiki K, Okada S.
  • Journal Title: Oncology Letters Volume: 16 Pages: 3923-3928
  • DOI: 10.3892/ol.2018.9132
  • Peer Reviewed / Open Access
• [Journal Article] Dual Threat of Epstein-Barr Virus: an Autopsy Case Report of HIV-Positive Plasmablastic Lymphoma Complicating EBV-Associated Hemophagocytic Lymphohistiocytosis (2018)
  • Author(s): Koizumi Yusuke、Imadome Ken-Ichi、Ota Yasunori、Minamiguchi Hitoshi、Kodama Yoshinori、Watanabe Dai、Mikamo Hiroshige、Uehira Tomoko、Okada Seiji、Shirasaka Takuma
  • Journal Title: Journal of Clinical Immunology Volume: 印刷中 Issue: 4 Pages: 478-483
  • DOI: 10.1007/s10875-018-0500-4
  • Peer Reviewed
• [Journal Article] Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1 JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3 ?/? mice transplanted with human PBMCs (2018)
  • Author(s): Ogata-Aoki Hiromi、Higashi-Kuwata Nobuyo、Hattori Shin-ichiro、Hayashi Hironori、Danish Matthew、Aoki Manabu、Shiotsu Chiemi、Hashiguchi Yumi、Hamada Akinobu、Kobayashi Hisataka、Ihn Hironobu、Okada Seiji、Mitsuya Hiroaki
  • Journal Title: Antiviral Research Volume: 149 Pages: 78-88
  • DOI: 10.1016/j.antiviral.2017.09.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment of a Patient-Derived Tumor Xenograft Model and Application for Precision Cancer Medicine (2018)
  • Author(s): Seiji Okada, Kulthida Vaeteewoottacharn, Ryusho Kariya
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 66 Issue: 3 Pages: 225-230
  • DOI: 10.1248/cpb.c17-00789
  • NAID: 130006407124
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Primary Effusion Lymphomaの発症機序と治療の進歩 (2018)
  • Author(s): 岡田誠治
  • Journal Title: 血液内科 Volume: 76 Pages: 334-339
• [Journal Article] Activation of Vimentin is Critical to Promote a Metastatic Potential of Cholangiocarcinoma Cells (2017)
  • Author(s): Saentaweesuk Waraporn、Araki Norie、Vaeteewoottacharn Kulthida、Silsirivanit Atit、Seubwai Wunchana、Talabnin Chutima、Muisuk Kanha、Sripa Banchob、Wongkham Sopit、Okada Seiji、Wongkham Chaisiri
  • Journal Title: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics Volume: 印刷中 Issue: 4 Pages: 605-616
  • DOI: 10.3727/096504017x15009778205068
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma (2017)
  • Author(s): Goto H、Kariya R、Kudo E、Okuno Y、Ueda K、Katano H、Okada S
  • Journal Title: Oncogene Volume: 36 Issue: 37 Pages: 5252-5262
  • DOI: 10.1038/onc.2017.138
  • Peer Reviewed
• [Journal Article] YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma. (2017)
  • Author(s): Kojima Y, Hayakawa F, Morishita T, Sugimoto K, Minamikawa Y, Iwase M, Yamamoto H, Hirano D, Imoto N, Shimada K, Okada S, Kiyoi H
  • Journal Title: Pharmacol Res. Volume: in press Pages: 242-251
  • DOI: 10.1016/j.phrs.2017.04.006
  • Peer Reviewed / Open Access
• [Journal Article] Repurposing cimetidine for cholangiocarcinoma: antitumor effects in vitro and in vivo (2017)
  • Author(s): Dana P, Vaeteewoottacharn K, Kariya R, Matsuda K, Wongkham S, and Okada S.
  • Journal Title: Oncol Lett Volume: 13 Issue: 3 Pages: 1432-1436
  • DOI: 10.3892/ol.2017.5563
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early phase dynamics of traceable mCherry fluorescent protein-carrying HIV-1 infection in human peripheral blood mononuclear cells-transplanted NOD/SCID/Jak3 -/- mice (2017)
  • Author(s): Higashi-Kuwata Nobuyo、Ogata-Aoki Hiromi、Hattori Shin-ichiro、Hayashi Hironori、Danish Matthew、Aoki Manabu、Shiotsu Chiemi、Kawamura Tatsuyoshi、Ihn Hironobu、Kobayashi Hisataka、Okada Seiji、Mitsuya Hiroaki
  • Journal Title: Antiviral Research Volume: 144 Pages: 83-92
  • DOI: 10.1016/j.antiviral.2017.03.027
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Application of highly immunodeficient mice for biomedical research. (2017)
  • Author(s): 岡田 誠治
  • Journal Title: Cytometry Research Volume: 27 Issue: 1 Pages: 25-31
  • DOI: 10.18947/cytometryresearch.27.1_25
  • NAID: 130006832442
  • ISSN: 0916-6920, 2424-0664
  • Open Access
• [Journal Article] Correlation between Histone Acetylation and Expression of Notch1 in Human Lung Carcinoma and Its Possible Role in Combined Small Cell Lung Carcinoma. (2017)
  • Author(s): Hassan, W., Takebayashi, S. I., Abdalla, M. O., Fujino, K., Kudoh, S., Motooka, Y., Sato, Y., Naito, Y., Higaki, K., Wakimoto, J., Okada, S., Nakao, M., Ishikawa, Y., and Ito, T.
  • Journal Title: Lab. Invest. Volume: 印刷中 Issue: 8 Pages: 913-921
  • DOI: 10.1038/labinvest.2017.36
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma. (2017)
  • Author(s): Goto H, Kariya R, Kudo E, Okuno Y, Ueda K, Katano H and Okada S
  • Journal Title: Oncogene Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Upregulation of CD147 Promotes Metastasis of Cholangiocarcinoma by Modulating the Epithelial-to-Mesenchymal Transitional Process. (2017)
  • Author(s): Dana P, Kariya R, Vaeteewoottacharn K, Sawanyawisuth K, Seubwai W, Matsuda K, Okada S, and Wongkham S.
  • Journal Title: Oncol Res Volume: 印刷中 Issue: 7 Pages: 1047-1059
  • DOI: 10.3727/096504016x14813899000565
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] nhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress. (2016)
  • Author(s): Masud Alam M, Kariya R, Kawaguchi A, Matsuda K, Kudo E, Okada S.
  • Journal Title: Apoptosis. Volume: 10 Issue: 10 Pages: 1191-1201
  • DOI: 10.1007/s10495-016-1277-7
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a novel human cholangiocarcinoma cell line with high metastatic activity. (2016)
  • Author(s): Uthaisar K, Vaeteewoottacharn K, Seubwai W, Talabnin C, Sawanyawisuth K, Obchoei S, Kraiklang R, Okada S, Wongkham S.
  • Journal Title: Oncol Rep Volume: 36 Issue: 3 Pages: 1435-1446
  • DOI: 10.3892/or.2016.4974
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] TAS4464, NEDD8 activating enzyme inhibitor, induces apoptosis for Primary effusion lymphoma cells (2018)
  • Author(s): Seiji Okada, Ryusho Kariya, HIromi Muraoka, Chieko Yoshimura, Eriko Kudo
  • Organizer: 37th World Congress of the International Society of Hematology
  • Int'l Joint Research
• [Presentation] SLAMF7 (CD319/CS1): A Potential New Therapeutic Target for the Treatment of Primary Effusion Lymphoma (2018)
  • Author(s): Jutatip Panaampon, Ryusho Kariya, Seiji Okada
  • Organizer: 37th World Congress of the International Society of Hematology
  • Int'l Joint Research
• [Presentation] Evaluation of therapeutic antibodies for malignant lymphoma using immunocompromised mouse model. (2018)
  • Author(s): Seiji Okada
  • Organizer: 7th Federation of Immunological Societies of Asia-Oceania (FIMSA) Congress 2018
  • Int'l Joint Research / Invited
• [Presentation] PAX5 acts as a tumor suppressor by regulating cell cycle in primary effusion lymphoma (2018)
  • Author(s): Hiroki Goto, Ryusho Kariya, Seiji Okada
  • Organizer: The 2nd JSPS&NUS Joint Symposium
  • Int'l Joint Research
• [Presentation] Application of novel highly immunodeficient mice for patient derived xenograft (PDX) model and evaluation of anticancer therapy (2017)
  • Author(s): Seiji Okada, Kulthida Vaeteewoottacahrn, Hiroki Goto, and Ryusho Kariya
  • Organizer: 3rd International Symposium for Medicinal Sciences
  • Place of Presentation: 仙台国際センター 仙台
  • Year and Date: 2017-03-24
  • Int'l Joint Research / Invited
• [Presentation] クロロゲン酸の原発性滲出性悪性リンパ腫に対する抗腫瘍効果の検討 (2017)
  • Author(s): 刈谷龍昇, Ployplon Phikulsod, 川口梓, Jutatip Panaampon, Md. Masud Alam, 岡田誠治
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台国際センター 仙台
  • Year and Date: 2017-03-24
• [Presentation] 高度免疫不全マウスを用いた患者腫瘍移植マウスモデル(Patient-Derived Tumor Xenograft: PDX) の樹立とその活用 －個別化がん治療(Precision Cancer Medicine)に向けて－ (2017)
  • Author(s): 岡田誠治
  • Organizer: 第27回日本サイトメトリー学会学術集会
  • Invited
• [Presentation] Establishment and application of Primary effusion lymphoma mice model (2017)
  • Author(s): Seiji Okada
  • Organizer: 20th International Workshop on Kaposi’s Sarcoma Herpes Virus (KSHV) and Related Agents
  • Int'l Joint Research
• [Presentation] Role of PU.1 Down-Regulation for the Development of Primary Effusion Lymphoma (2016)
  • Author(s): Hiroki Goto, Ryusho Kariya, Eriko Kudo, Yutaka Okuno, and Seiji Okada
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Induction of apoptosis by Shikonin through a ROS/JNK mediated process in primary effusion lymphoma (2016)
  • Author(s): Md. Masud Alam, Ryusho Kariya, Azusa Kawaguchi, and Seiji Okada
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-10-13
• [Presentation] がん関連繊維芽細胞分化抑制剤の探索 (2016)
  • Author(s): 刈谷龍昇、Dana Paweena、松田幸樹、Masud Alam、川口梓、岡田誠治
  • Organizer: 第26回日本サイトメトリー学会
  • Place of Presentation: 九州大学医学部百年講堂、福岡
  • Year and Date: 2016-07-23
• [Presentation] シコニンの原発性滲出液悪性リンパ腫に対する抗腫瘍効果について (2016)
  • Author(s): 川口梓、刈谷龍昇、Masud Alam、岡田誠治
  • Organizer: 第26回日本サイトメトリー学会
  • Place of Presentation: 九州大学医学部百年講堂、福岡
  • Year and Date: 2016-07-23
• [Remarks] 熊本大学エイズ学研究センター岡田研究室
  • URL: http://www.caids.kumamoto-u.ac.jp/data/okada/default.html
• [Remarks] 岡田 誠治 ｜ 研究紹介 ｜ がん研究分野の特性等を踏まえた支援活動
  • URL: http://ganshien.umin.jp/research/spotlight/okada/index.html
• [Remarks] 【KUMADAI NOW】 岡田 誠治 教授（エイズ学研究センター）
  • URL: https://www.youtube.com/watch?v=RJNjHjMKzHU
• [Remarks] 岡田 誠治 — Kumamoto University
  • URL: https://kumamoto.pure.elsevier.com/ja/persons/seiji-okada