Multifunctional role of Membrane-type 1 matrix metalloproteinase in multiple myeloma

• Project/Area Number: 24591382
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: HEISSIG Beate 東京大学, 医科学研究所, 准教授 (30372931)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 生体・分子 / 細胞・組織 / 発現制御 / 酵素 / 生体分子 / 発言制御 / CXCL12 / Kit-ligand / 血管新生 / 細胞外ドメイン分泌 / 遺伝子発現 / HIF-1 / FIH-1 / PAI-1阻害剤

Outline of Final Research Achievements

Multiple myeloma (MM) is a B-cell malignancy characterized by the monoclonal proliferation of plasma cells in the bone marrow (BM). In the initial stages of disease establishment, MM cells reside in a hypoxic BM microenvironment. The long-term objective of this proposal is to examine the role of membrane type-1-matrix metalloproteinase (MT1-MMP) in the regulation of normal B cell development and malignant plasma cell growth in models of MM. MT1-MMP is expressed in MM cells, and cells of the MM microenvironment. Stroma cells produce cytokines. MT1-MMP is required for normal B cell development. Mechanistically we showed that MT1-MMP drives HIF-1-mediated activation of cytokines like Kit ligand, stromal cell-derived factor-1, and interleukin-7. Most cell line-based MM models show BM infiltration of MM cells. We established a novel murine model that mimics various aspects of clinical signs of MM, which will help to understand the interaction between malignant plasma and stroma cells.

Research Products

• [Journal Article] Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. (2015)
  • Author(s): A Sato, C Nishida, K Sato-Kusubata, M Ishihara, Y Tashiro, I Gritli, H Shimazu, S Munakata, H Yagita, K Okumura, Y Tsuda, Y Okada, A Tojo, H Nakauchi, S Takahashi, B Heissig and K Hattori
  • Journal Title: Leukemia Volume: 29 Issue: 1 Pages: 145-56
  • DOI: 10.1038/leu.2014.151
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9-Mediated Cytokine Release From Myeloid Cells. (2015)
  • Author(s): Munakata S, Tashiro Y, Nishida C, Sato A, Komiyama H, Shimazu H, Dhahri D, Salama Y, Eiamboonsert S, Takeda K, Yagita H, Tsuda Y, Okada Y, Nakauchi H, Sakamoto K, Heissig B, Hattori K.
  • Journal Title: Gastroenterology Volume: 148 Issue: 3 Pages: 565-78
  • DOI: 10.1053/j.gastro.2014.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells. (2014)
  • Author(s): Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D, Matsukawa T, Kagiyama Y, Enomoto Y, Kawabata KC, Chen-Yi L, Komeno Y, Izawa K, Oki T, Nagae G, Harada Y, Harada H, Otsu M, Aburatani H, Heissig B, Hattori K, Kitamura T.
  • Journal Title: Blood Volume: 123(25) Issue: 25 Pages: 3932-42
  • DOI: 10.1182/blood-2013-01-476747
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MT1-MMP plays a critical role in henatopoiesis by regulating HIF-mediated chemo-/cytokine gene transcription within niche cells. (2012)
  • Author(s): Chiemi Nishida, Kaori Kusubata, Yoshihiko Tashiro, Ismael Gritli, Aki Sato, Makiko Ohki-Koizumi, Yohei Morita, Makoto Nagano, Takeharu Sakamoto, Naohiko Koshikawa, Takahiro Kuchimaru, Shinae Kizaka-Kondoh, Motoharu Seiki, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori.
  • Journal Title: Blood Volume: 119 Issue: 23 Pages: 5404-5416
  • DOI: 10.1182/blood-2011-11-390849
  • Peer Reviewed
• [Journal Article] Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice (2012)
  • Author(s): Yoshihiko Tashiro, Chiemi Nishida, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Makoto Ishihara, Aki Sato, Ismael Gritli, Hiromitsu Komiyama, Yayoi Sato, Takashi Dan, Toshio Miyata, Ko Okumura, Yuichi Tomiki, Kazuhiro Sakamoto, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori.
  • Journal Title: Blood Volume: 119 Issue: 26 Pages: 6382-6393
  • DOI: 10.1182/blood-2011-12-399659
  • Peer Reviewed
• [Presentation] Mesenchymal Stem Cells expansion by the fibrinolytic system: implications in the cancer microenvironment. (2015)
  • Author(s): Douaa Dhahri, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Chiemi Nishida, Hiromitsu Nakauchi, Koichi Hattori and Beate Heissig.
  • Organizer: Gordon Research Conferences "Stem Cells & Cancer"
  • Place of Presentation: Ventura, CA, USA.
  • Year and Date: 2015-02-15 – 2015-02-20
• [Presentation] The fibrinolytic system modulates the cytokine and cellular environment during cancer progression and chronic inflammation. (2015)
  • Author(s): Beate Heissig
  • Organizer: Joint International Symposium on TGF-β and Cancer
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2015-01-12 – 2015-01-13
  • Invited
• [Presentation] Mesenchymal Stem Cells expansion by the fibrinolytic system: implications in cancer microenvironment. (2015)
  • Author(s): Douaa Dhahri, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Chiemi Nishida, Koichi Hattori and Beate Heissig.
  • Organizer: Joint International Symposium on TGF-β and Cancer
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2015-01-12 – 2015-01-13
• [Presentation] Epidermal Growth Factor-like Domain 7 Promotes Hematopoietic Stem Cell Expansion and Increases Myeloid-Megakaryocytic Lineage Priming through beta3 Integrin. (2014)
  • Author(s): Chiemi Nishida, Yousef Salama, Ismael Gritli, Terumasa Umemoto, Hiromitsu Nakauchi, Koichi Hattori, Beate Heissig.
  • Organizer: 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, California, USA.
  • Year and Date: 2014-12-04 – 2014-12-09
• [Presentation] EGFL7 regulates hematopoietic stem/progenitor cell fate in the bone marrow niche through β3 integrin. (2014)
  • Author(s): Yousef Salama, Chiemi Nishida, Ismael Gritli, Terumasa Umemoto, Hiromitsu Nakauchi, Koichi Hattori, Beate Heissig.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] The fibrinolytic pathway is required for Mesenchymal Stem Cell expansion by initiating a crosstalk between Mesenchymal Stem and Endothelial cells. (2014)
  • Author(s): Beate Heissig, Douaa Dhahri , Chiemi Nishida , Kaori Kusubata , Makiko Ohki-Koizumi , Koichi Hattori.
  • Organizer: The 18th International Vascular Biology Meeting (IVBM 2014)
  • Place of Presentation: みやこめっせ（京都府京都市）
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] EGFL7 recruits quiescent HSCs into active cell cycle and expands HSCs. (2014)
  • Author(s): Chiemi Nishida, Yousef Salamam, Koichi Hattori , Beate Heissig.
  • Organizer: The 18th International Vascular Biology Meeting (IVBM 2014)
  • Place of Presentation: みやこめっせ（京都府京都市）
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] MT1-MMP plays a critical role in chemo-/cytokine expression by regulating HIF activation. (2014)
  • Author(s): Chiemi Nishida, Beate Heissig, Koichi Hattori.
  • Organizer: The 18th International Vascular Biology Meeting (IVBM 2014)
  • Place of Presentation: みやこめっせ（京都府京都市）
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] 造血微小環境におけるMT1-MMPと造血因子の発現調節 (2013)
  • Author(s): 西田知恵美
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: 横浜市
• [Presentation] Recruitment of Hematopoietic Progenitor and Stem Cells is Regulated by the Angiogenic Factor Epidermal Growth Factor- like Domain 7 (2013)
  • Author(s): Ismael Gritli
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: 横浜市
• [Presentation] MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemo-/cytokine gene transcription within niche cells (2012)
  • Author(s): Chiemi Nishida
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: Atlanta USA
• [Presentation] MT1-MMP REGULATES HEMATOPOIESIS THROUGH HIF-MEDIATED CHEMO-/CYTOKINE RELEASE FROM THE BONE MARROW NICHE, (2012)
  • Author(s): Chiemi Nishida
  • Organizer: 第10回国際幹細胞学会
  • Place of Presentation: 横浜市
• [Presentation] F-2214-Expansion of Mesenchymal Stem Cells Wishin The Murine Bone Marrow Niche Rwquires Activation of The Fibrinolytic Pathway (2012)
  • Author(s): Sato-KusubataKaori
  • Organizer: 第10回国際幹細胞学会
  • Place of Presentation: 横浜市
• [Presentation] MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated cytokine gene transcription (2012)
  • Author(s): Chiemi Nishida
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都市
• [Presentation] Aplasmin inhibitor prevents cytokine mediated inflammatory disease (2012)
  • Author(s): Aki Sato
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都市
• [Presentation] MT1-MMP REGULATES HEMATOPOIESIS THROUGH HIF-MEDIATED CHEMO-/CYTOKINE RELEASE FROM THE BONE MARROW NICHE
  • Author(s): Chiemi Nishida
  • Organizer: 第12回東京大学生命科学シンポジウム
  • Place of Presentation: 東京都
• [Presentation] Expansion of mesenchymal stem cells within the murine bone marrow niche requires activation of the fibrinolytic pathway
  • Author(s): 楠畑かおり
  • Organizer: 第12回東京大学生命科学シンポジウム
  • Place of Presentation: 東京都
• [Presentation] 第11回日本再生医療学会
  • Author(s): 西田知恵美
  • Organizer: 第11回日本再生医療学会
  • Place of Presentation: 横浜市
• [Book] 実験医学増刊 Vol.33 No.5 （がん微小環境と標的治療） (2015)
  • Author(s): ハイジッヒ・ベアテ、服部浩一
  • Total Pages: 6
  • Publisher: 羊土社
• [Remarks] 東京大学医科学研究所 幹細胞治療研究センター 幹細胞ダイナミクス解析分野
  • URL: http://stemcell-u-tokyo.org/scd/
• [Remarks] 幹細胞治療研究センター 幹細胞ダイナミクス解析分野
  • URL: http://stemcell-u-tokyo.org/scd/
• [Remarks] 東京大学医科学研究所 幹細胞ダイナミクス解析分野
  • URL: http://stemcell-u-tokyo.org/scd/