Mechanisms of induction of cancer stem cells in the bone microenvironment ; involvement of drug resistance for bone metastasis

• Project/Area Number: 15K06837
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Nagasaki University (2017); Nagoya City University (2015-2016)
• Principal Investigator: FUTAKUCHI Mitsuru 長崎大学, 病院(医学系), 准教授 (60275120)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); 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: Bone microenvironment / TGF-beta / Cancer stem cell / 骨微小環境 / がん幹細胞 / 動物モデル / 骨転移 / 乳がん

Outline of Final Research Achievements

In the present study, anti bone metastasis agents which have different targets, was examined to identify the mechanisms for the induction of CSCs in the bone MI. Treatment of bone modifying agents, targeting osteoclasts, did not change the ratio of CSCs in the bone ME as well as subQ ME and treatment of TGFβ signaling inhibitor, significantly reduced that of CSC in the bone ME. Interestingly, inappropriate treatments of anti cancer agent or androgen, targeting prostate cancer cells, significantly increased the ratio of CSCs in the bone ME in our model using androgen independent or dependent prostate cancer cells. Our results indicated that bone MI would be good niche for CSCs, and TGFβ would be involved in the induction of CSCs, and anti-cancer agents combined with those targeting CSC may plays a key role to eliminate the drug resistant bone metastasis of prostate or breast cancer.

Research Products

• [Int'l Joint Research] Institute of Surgical Research/Faculty of Medicine/University of Szeged(Hungary)
• [Int'l Joint Research] Institute of Surgical Research/Faculty of Medicine/University of Szeged(ハンガリー)
• [Journal Article] Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A (2018)
  • Author(s): Kyoko Hashimoto, Hiroki Ochi, Satoko Sunamura, Nobuyoshi Kosaka, Yo Mabuchi, Toru Fukuda, Kenta Yao, Hiroaki Kanda, Keisuke Ae, Atsushi Okawa, Chihiro Akazawa, Takahiro Ochiya, Mitsuru Futakuchi, Shu Takeda, Shingo Sato
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 115(9) Issue: 9 Pages: 2204-2209
  • DOI: 10.1073/pnas.1717363115
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic and Preventive Effects of Osteoclastogenesis Inhibitory Factor on Osteolysis, Proliferation of Mammary Tumor Cell and Induction of Cancer Stem Cells in the Bone Microenvironment (2018)
  • Author(s): Futakuchi, M. Nitanda, T. Ando, S. Matsumoto, H. Yoshimoto, E. Fukamachi, K. Suzui, M.
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 3 Pages: 888-888
  • DOI: 10.3390/ijms19030888
  • NAID: 120006987309
  • Peer Reviewed / Open Access
• [Journal Article] Development of Oral Squamous Cell Carcinoma (OSCC) with Enhanced Metastatic Potential Through Loss of NDRG2 Expression. (2017)
  • Author(s): Tamura, T., Ichikawa, T., Nakahata, S., Kondo, Y., Tagawa, Y., Yamamoto, K., Nagai, K., Baba, T., Yamaguchi, R., Futakuchi, M., Yamashita, Y., and Morishita, K.
  • Journal Title: Cancer Res Volume: 印刷中 Issue: 9 Pages: 2363-2374
  • DOI: 10.1158/0008-5472.can-16-2114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. (2017)
  • Author(s): Li GH, Akatsuka S, Chew SH, Jiang L, Nishiyama T, Sakamoto A, Takahashi T, Futakuchi M, Suzuki H, Sakumi K, Nakabeppu Y, Toyokuni S.
  • Journal Title: Pathol Int. Volume: 67 Issue: 11 Pages: 564-574
  • DOI: 10.1111/pin.12598
  • NAID: 120006382249
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel monoclonal antibody targeting coxsackie virus and adenovirus receptor inhibits tumor growth in vivo. (2017)
  • Author(s): Kawada, M., Inouea, H., Kajikawa, M., Sugiura, M., Sakamoto, S., Urano, S., Karasawa, C., Usami, I., Futakuchi, M., and Masuda, T.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 40400-40400
  • DOI: 10.1038/srep40400
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Multiwalled carbon nanotubes intratracheally instilletd into the rat lung induce development of pleural malignant mesothelioma and lung tumors. (2016)
  • Author(s): 1.Suzui M, Futakuchi M, Fukamachi K, Numano T, Abd Elgied M, Takahashi S, Ohnishi M, Omori T, Tsuruoka S, Hirose A, Kanno J, Sakamoto Y, Alexander DB, Xu J, Tsuda H.
  • Journal Title: Cancer Sci Volume: 107 Issue: 7 Pages: 924-935
  • DOI: 10.1111/cas.12954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer (2016)
  • Author(s): Futakuchi, M.*, Fukamachi, K., and Suzui, M.
  • Journal Title: Advanced Drug Delivery Reviews Volume: 99 Pages: 206-211
  • DOI: 10.1016/j.addr.2015.11.017
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] C5a inhibitor protects ischemia/reperfusion injury in rat small intestine. (2015)
  • Author(s): Tuboly E, Futakuchi M, Varga G, Erces D, Tokes T, Meszaros A, Kaszaki J, Suzui M, Imai M, Okada A, Okada N, Boros M, Okada H.
  • Journal Title: Microbiology and Immunology, Epub Volume: 60 Issue: 1 Pages: 35-46
  • DOI: 10.1111/1348-0421.12338
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemokine (C-C motif) ligand 3 detection in the serum of persons exposed to asbestos: A patient-based study (2015)
  • Author(s): Xu, J., Alexander, D. B., Iigo, M., Hamano, H., Takahashi, S., Yokoyama, T., Kato, M., Usami, I., Tokuyama, T., Tsutsumi, M., Tamura, M., Oguri, T., Niimi, A., Hayashi, Y., Yokoyama, Y., Tonegawa, K., Fukamachi, K., Futakuchi, M.,et al.
  • Journal Title: Chemokine (C-C motif) ligand 3 detection in the serum of persons exposed to asbestos: A patient-based study Volume: 106 Issue: 7 Pages: 2112-2118
  • DOI: 10.1111/cas.12687
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In vivo 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography imaging of pancreatic tumors in a transgenic rat model carrying the human KRASG12V oncogene. (2015)
  • Author(s): Shibata, K., Fukamachi, K., Tsuji, T., Saga, T., Futakuchi, M., Nagino, M., Tsuda, H., and Suzui, M.
  • Journal Title: Oncology Letters Volume: 9 Pages: 2112-2118
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles. (2014)
  • Author(s): Arimoto KI, Hishiki T, Kiyonari H, Abe T, Cheng C, Yan M, Fan JB, Futakuchi M, Tsuda H, Murakami Y, Suzuki H, Zhang DE, Shimotohno K
  • Journal Title: J Interferon Cytokine Res. Volume: 35 Issue: 5 Pages: 351-358
  • DOI: 10.1089/jir.2014.0113
  • Peer Reviewed
• [Presentation] 先端モデル動物プラットフォーム 病理形態支援班の内容について (2017)
  • Author(s): 二口 充
  • Organizer: 生命科学連携推進協議会「生命科学4プラットフォーム説明会・成果シンポジウム」
  • Invited
• [Presentation] 「ちょっと、これ診てくれませんか？」 (2017)
  • Author(s): 二口 充
  • Organizer: 先端モデル動物プラットフォーム 若手支援技術講習会2017
  • Invited
• [Presentation] Heterogeneity of tumor cells in the bone microenvironment; mechanisms and therapeutic targets of bone metastasis (2016)
  • Author(s): Mitsuru Futakuchi, Katsumi Fukamachi and Masumi Suzui
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Pacifico Yokohama, Yokohama（Japan）
  • Year and Date: 2016-10-06
  • Int'l Joint Research
• [Presentation] 骨微小環境における前立腺がんおよび乳がんの増殖機構と治療標的因子 (2016)
  • Author(s): 二口 充
  • Organizer: 第13回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（兵庫県、神戸市）
  • Year and Date: 2016-07-29
  • Invited
• [Presentation] 骨微小環境における前立腺癌および乳がんの増殖機構 (2016)
  • Author(s): 二口 充
  • Organizer: 第28回Bone Research Meeting
  • Place of Presentation: 大阪大学銀杏会館（大阪府, 吹田市）
  • Year and Date: 2016-06-15
  • Invited
• [Presentation] 骨微小環境における乳がん細胞の増殖機構：骨転移巣の進展におけるがん幹細胞の関与 (2016)
  • Author(s): 二口 充
  • Organizer: 第105回日本病理学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 骨微小環境における乳がん細胞の増殖機構：骨転移巣の進展におけるがん幹細胞の関与 (2016)
  • Author(s): 二口 充
  • Organizer: 第105回日本病理学会学術総会
  • Place of Presentation: 仙台国際センター（宮城県, 仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 骨転移を形成するがんの不均一性：その増殖メカニズムと治療標的因子 (2016)
  • Author(s): 二口 充
  • Organizer: 第28回 Bone Research Joint Meeting
  • Place of Presentation: 大阪大学銀杏会館（大阪府吹田市）
  • Invited
• [Presentation] 骨微小環境に特異的ながん細胞増殖メカニズム：新たな治療標的分子の同定へ (2016)
  • Author(s): 二口 充
  • Organizer: 第19回癌と骨病変研究会
  • Place of Presentation: 千代田放送会館(東京都千代田区)
  • Invited
• [Presentation] Cancer stem cell in the bone microenvironment; therapeutic targets for bone metastasis of breast cancer (2015)
  • Author(s): Futakuchi, M
  • Organizer: The 20th Korea- Japan Cancer Research Workshop
  • Place of Presentation: ロイヤルパークザ汐留（東京都港区）
  • Year and Date: 2015-11-30
  • Int'l Joint Research / Invited
• [Presentation] 骨微小環境におけるがん細胞の増殖に関与するmicroRNAの同定とその機能解析：がん幹細胞の関与 (2015)
  • Author(s): 二口 充, 深町勝己, 酒々井眞澄
  • Organizer: 第24回日本がん転移学会学術総会
  • Place of Presentation: シティプラザ大阪（大阪府, 大阪市）
  • Year and Date: 2015-07-23
• [Presentation] 骨転移巣を形成するがん細胞の悪性形質を規程するmicroRNAの同定とその機能解析 (2015)
  • Author(s): 二口 充
  • Organizer: 第104回日本病理学会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-04-30
• [Book] 慢性炎症とがん (2016)
  • Author(s): 二口 充, 他
  • Total Pages: 172
  • Publisher: 北隆館
• [Book] 新臨床腫瘍学（改訂第４版）がん薬物療法専門医のために (2015)
  • Author(s): 二口 充, 他
  • Total Pages: 764
  • Publisher: 南光堂