The coagulation and the fibrinolytic system are essential drivers in the pathogenesis of leukemia and lymphoma

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591371
• 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: HATTORI Koichi 東京大学, 医科学研究所, 特任准教授 (10360116)
• Project Period (FY): 2011 – 2013
• Keywords: 血液内科学 / 癌 / 酵素 / 生体分子 / 生理活性 / 発生・分化

Research Abstract

The main coagulation and fibrinolytic factor plasmin, which is derived from its proform plasminogen (Plg) and one of its downstream targets, matrixmetalloproteinases (MMP), have been linked to various malignancies. Here, we provide the evidence that blockade of plasmin reduces lymphoma growth by inhibiting MMP-dependent recruitment of bone marrow derived CD11b+ cells locally within the lymphoma tissue. Genetic Plg deficiency and drug-mediated plasmin blockade delayed lymphoma growth and diminished MMP dependent marrow derived CD11b+ cell infiltration into lymphoma tissues and formation of malignant niche. We could show that CD11b+ cells play key a role in the growth of lymphoma and the other malignancies through malignant niche formation. Collectively, our data demonstrate a previously undescribed role of fibrinolytic system in tumor growth and provide strong evidence that specific blockade of plasmin a promising approach for the cancer treatments.

Research Products

• [Journal Article] Bonemarrow-derived CD11b+Jagged-2+ cells promote epithelial to mesenchymal transition and metastization in colorectal cancer (2013)
  • Author(s): Caiado F, Carvalho T, Rosa I, Remedio L, Costa A, Matos J, Heissig B, Yagita H, Hattori K, da Silva JP, Fidalgo P, Dias Pereira A, Dias S
  • Journal Title: Cancer Res Volume: 73(14) Pages: 4233-46
  • DOI: 10.1158/0008-5472.CAN-13-0085
• [Journal Article] MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemo-/cytokine gene transcription within niche cells (2012)
  • Author(s): Nishida C, Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M, Morita Y, Nagano M, Sakamoto T, Koshikawa N, Kuchimaru T, Kizaka-Kondoh S, Seiki M, Nakauchi H, Heissig B, and Hattori K
  • Journal Title: Blood Volume: 119(23) Pages: 5405-5416
  • DOI: 10.1182/blood-2011-11-390849
• [Journal Article] Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice (2012)
  • Author(s): Tashiro Y, Nishida C, Sato-Kusubata K, Ohki-Koizumi M, Ishihara M, Sato A, Gritli I, Komiyama H, Sato Y, Tomiki Y, Sakamoto H, Dan T, Miyata T, Okumura K, Nakauchi H, Heissig B, and Hattori K
  • Journal Title: Blood Volume: 119(26) Pages: 6382-6393
  • DOI: 10.1182/blood-2011-12-399659
• [Journal Article] Plasminogen deficiency attenuates post-natal erythropoiesis in male C57BL/6 mice through decreased activity of the LH-testosterone axis (2012)
  • Author(s): Okaji Y, Tashiro Y, Gritli I, Nishida C, Sato A, Ueno Y, Del Canto Gonzalez S, Ohki-Koizumi M, Akiyama H, Nakauchi H, Heissig B, Hattori K
  • Journal Title: Exp Hematol Volume: Vol 40 Pages: 143-154
  • DOI: 10.1016/j.exphem.2011.10.008
• [Journal Article] Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b^+/F4/80^+ myeloid cell recruitment (2012)
  • Author(s): Ishihara M, Nishida C, Tashiro Y, Gritli I, Rosenkvist J, Koizumi M, Yamamoto R, Yagita H, Okumura K, Nishikori M, Wanaka K, Tsuda Y, Okada Y, Nakauchi H, Heissig B, Hattori K
  • Journal Title: Leukemia Volume: 26 Pages: 332-339
  • DOI: 10.1038/leu.2011.203
• [Journal Article] Tumor necrosis receptor-associated factor (Traf)2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease (2011)
  • Author(s): Piao JH, Hasegawa M, Heissig B, Hattori K, Takeda K, Iwakura Y, Okumura K, Inohara N, Nakano H
  • Journal Title: J Biol Chem Volume: 151 Pages: 17879-17888
  • DOI: 10.1074/jbc.P111.221853
• [Presentation] EGFL7 recruits quiescent HSCs into active cell cycle and expands HSCs (2014)
  • Author(s): Salama Y、西田知恵美、Gritli I、Dhari D、Eiamboonsert S、中内啓光、Heissg B服部浩一
  • Organizer: 13回日本再生医療学会
  • Place of Presentation: 京都国際会館、京都
  • Year and Date: 2014-03-06
• [Presentation] プラスミン阻害剤による炎症性腸疾患に対する腸管上皮保護と再生促進作用 (2014)
  • Author(s): 宗像慎也、田代良彦、小見山博光、島津浩、佐藤亜紀、西田知恵美、坂本一博、Heissig Beate、服部浩一
  • Organizer: 第13回日本再生医療学会
  • Place of Presentation: 京都国際会館、京都
  • Year and Date: 2014-03-05
• [Presentation] Plasmin inhibitor prevents acute graft-versus-host disease (2013)
  • Author(s): Sato A, Nishida C, Takahashi S, Tojo A, Nakauchi H, hiessig B, Hattori K
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌芸文館札幌市
  • Year and Date: 2013-10-12
• [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, Heissig B,服部浩一
  • Organizer: 第9回麒麟塾
  • Place of Presentation: 東京
  • Year and Date: 2013-07-14
• [Presentation] Protease activation triggers the process of tissue regeneration (2013)
  • Author(s): Hattori K
  • Organizer: The 8 th International Symposium of the Institute Network
  • Place of Presentation: 芝蘭会館、京都市
  • Year and Date: 2013-06-28
  • Invited
• [Presentation] 炎症性腸疾患における血液凝固・線維素溶解系の機能解明について (2013)
  • Author(s): 宗像慎也、Heissig B、服部浩一
  • Organizer: 第13回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学、東京都
  • Year and Date: 2013-06-08
• [Presentation] 血球貪食症候群における血液線維素溶解系からの機能解析 (2013)
  • Author(s): 島津浩、Heissig B、服部浩一
  • Organizer: 第13回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学、東京都
  • Year and Date: 2013-06-08
• [Presentation] Pharmacological Targeting of Plasmin Prevents Inflammatory Diseases Like Septic Shock and Acute Graft-versus-host Disease (2013)
  • Author(s): Sato A.Heissig B.Hattori K
  • Organizer: XIVth International Workshop Molecular & Cellular Biology of Plasminogen Activation
  • Place of Presentation: University of Notre Dame Indiana USA
  • Year and Date: 2013-06-06
• [Presentation] The expansion of Mesenchymal Stem Cell by the fibrinolytic system involves a crosstalk with endothelial cells (2013)
  • Author(s): Dhahri D, Koizumi M, Kusubata k , Nishida C, Hattori K,Heissig B
  • Organizer: 平成25年度東京大学医科学研究所成果発表会
  • Place of Presentation: 東京大学、東京都(第二位)
  • Year and Date: 2013-05-31
• [Presentation] Pharmacological targeting of plasmin prevents macrophage activation syndrome in mice (2013)
  • Author(s): 島津浩、Dhahri D、Salama Y、宗像慎也、佐藤亜紀、C、西田知恵美、Heissig B服部浩一
  • Organizer: 平成25年度東京大学医科学研究所成果発表会
  • Place of Presentation: 東京大学、東京都(第一位)
  • Year and Date: 2013-05-31
• [Presentation] PAI-1阻害剤による血管新生及び組織再生促進療法 (2013)
  • Author(s): 宗像慎也,田代良彦,島津浩,西田知恵美,イスマエルグリツリ,佐藤亜紀,小泉摩季子,楠畑かおり,小見山博光,坂本一博,宮田敏男,ハイジッヒベアテ,服部浩一
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2013-04-11
• [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,楠畑かおり,田代良彦, Gritli, I佐藤亜紀,小泉(大木)摩季子,守田陽平,長野真,坂本毅治,口丸高弘.近藤科江,清木元治,中内啓光, Heissig B,服部浩一
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2013-03-22
• [Presentation] PAI-1阻害剤による血管新生及び組織再生促進療法 (2013)
  • Author(s): 田代良彦,宗像慎也,西田知恵美,石原誠人,Gritli I,島津浩,佐藤亜紀,楠畑かおり,小泉摩季子,小見山博光,坂本一博,宮田敏夫,中内啓光,Heissig B,服部浩一
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-22
• [Presentation] Recruitment of Hematopoietic Progenitor and Stem Cells is Regulated by the Angiogenic Factor Epidermal Growth Factor- like Domain 7 (2013)
  • Author(s): Gritli I, Nishida C, Sato A, Shimazu H, Munakata S, Heissig B, Hattori K
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2013-03-22
• [Presentation] MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemo-/cytokine gene transcription within niche cells (2012)
  • Author(s): Nishida C, Sato-Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M, Morita Y, Nagano M, Sakamoto T, Seiki M, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: Georgia World Congress Center Atlanta
  • Year and Date: 2012-12-09
• [Presentation] プロテアーゼ活性化を起点とした各種疾患病態制御機構 (2012)
  • Author(s): 服部浩一
  • Organizer: 環境医学研究会
  • Place of Presentation: 順天堂浦安病院.浦安市
  • Year and Date: 2012-11-30
• [Presentation] MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated cytokine gene transcription (2012)
  • Author(s): NishidaC, Sato-Kusubata K, TashiroY, Gritli I, Sato A, Ohki-Koizumi M, Morita Y, Nagano M ,Sakamoto T, Seiki M, Nakauchi H, Heissig, B Hattori K
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館、京都市
  • Year and Date: 2012-10-20
• [Presentation] Aplasmin inhibitor prevents cytokine mediated inflammatory disease (2012)
  • Author(s): Sato, A, Nishida C, Gritli I,Sato-Kusubata K, Yagita H, Okumura K, Tsuda Y,Okada Y , Takahashi S, Tojo A, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館、京都市
  • Year and Date: 2012-10-20
• [Presentation] プロテアーゼ活性化を起点としたがん増殖機構とその制御 (2012)
  • Author(s): 服部浩一
  • Organizer: お茶の水がん学アカデミア第87回集会
  • Place of Presentation: 順天堂大学東京都
  • Year and Date: 2012-09-26
• [Presentation] MT1-MMP REGULATES HEMATOPOIESIS THROUGH HIF-MEDIATED CHEMO-/CYTOKINE RELEASE FROM THE BONE MARROW NICHE (2012)
  • Author(s): Nishida C, Sato-Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M, Morita Y, Nagano M, Sakamoto T, Seiki M, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第12回東京大学生命科学シンポジウム
  • Place of Presentation: 東大(ポスター)
  • Year and Date: 2012-06-30
• [Presentation] Expansion of mesenchymal stem cells within the murine bone marrow niche requires activation of the fibrinolytic pathway (2012)
  • Author(s): 楠畑かおり、小泉摩希子、Heissig B、服部浩一
  • Organizer: 第12回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学、東京都(ポスター)
  • Year and Date: 2012-06-30
• [Presentation] MT1-MMP REGULATES HEMATOPOIESIS THROUGH HIF-MEDIATED CHEMO-/CYTOKINE RELEASE FROM THE BONE MARROW NICHE (2012)
  • Author(s): Nishida C, Sato-Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M, Morita, Y, Nagano M, Sakamoto T,Seiki M, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第10回国際幹細胞学会
  • Place of Presentation: パシフィコ横浜、横浜市(ポスター)
  • Year and Date: 2012-06-16
• [Presentation] F-2214-Expansion of Mesenchymal Stem Cells Wishin The Murine Bone Marrow Niche Rwquires Activation of The Fibrinolytic Pathway (2012)
  • Author(s): Sato-KusubataK,Oki-KoizumiM,Heissi gB,HattoriK
  • Organizer: 第10回国際幹細胞学会
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2012-06-16
• [Presentation] 生体内造血機構におけるMT1-MMPの機能解析 (2012)
  • Author(s): 西田知恵美,楠畑かおり,田代良彦,清木元治,中内啓光, Heissig B,服部浩一
  • Organizer: 第11回日本再生医療学会
  • Place of Presentation: パシフィコ横浜、横浜市(口演)
  • Year and Date: 2012-06-14
• [Presentation] 炎症性腸疾患における凝固・繊維素溶解系の機能解明 (2012)
  • Author(s): 宗像慎也、Heissig B、服部浩一
  • Organizer: 平成24年度東京大学医科学研究所研究成果発表会
  • Place of Presentation: (第一位)
  • Year and Date: 2012-06-01
• [Presentation] 血液線維素溶解系の活性化による骨髄間葉系幹細胞の増殖機構の解析 (2012)
  • Author(s): 楠畑かおり、小泉摩希子、Heissig B、服部浩一
  • Organizer: 平成24年度東京大学医科学研究所研究成果発表会
  • Place of Presentation: (第三位)
  • Year and Date: 2012-06-01
• [Presentation] プロテアーゼ活性を起点とした血球貪食症候群の病態解明・新規治療法への展望 (2012)
  • Author(s): 島津浩、Heissig B、服部浩一
  • Organizer: 平成24年度東京大学医科学研究所研究成果発表会
  • Year and Date: 2012-06-01
• [Presentation] プロテアーゼ活性を起点とした造血・組織再生機構 (2012)
  • Author(s): 服部浩一
  • Organizer: Small Meeting on Hematology
  • Place of Presentation: 東海大学伊勢原市
  • Year and Date: 2012-05-16
  • Invited
• [Presentation] MT1-MMP Regulates Hematopoiesis Through HIF-Mediated Chemo-/Cytokine Release From the Bone Marrow Niche (2011)
  • Author(s): Nishida C, Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M, Seiki M, Nakauchi H, Heissig B and Hattori K
  • Organizer: 53回アメリカ血液学会
  • Place of Presentation: サンディエゴSan Diego Convention Center
  • Year and Date: 20111210-13
• [Presentation] A plasmin Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice (2011)
  • Author(s): Sato A, Tashiro Y, Nishida C, Gritli I, Kusubata, K, Takahashi S, Nakauchi H, Heissig B, Hattori K
  • Organizer: 53回アメリカ血液学会
  • Place of Presentation: サンディエゴSan Diego Convention Center(ASH Abstract Achievement Award受賞)
  • Year and Date: 20111210-13
• [Presentation] 生体内組織再生における線維素溶解系因子PAI-1の機能解明 (2011)
  • Author(s): 田代良彦、西田知恵美、イスマイルグリツリ、小泉摩希子、佐藤弥生、ハイジッヒ・ベアテ、服部浩一
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2011-10-16
• [Presentation] 血液線維素溶解系因子による造血系細胞の動態制御機構 (2011)
  • Author(s): 服部浩一
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2011-10-15
  • Invited
• [Presentation] MT1- MMP plays a critical role in the modulation of hematopoiesis (2011)
  • Author(s): Nishida C, Kusubata K, Seiki M, NakauchiN,HeissigB ,HattoriK
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2011-10-15
• [Presentation] Aplasmin inhibitor prevents lethal acute graft-versus-host disease in mice (2011)
  • Author(s): Sato A,Tashiro Y,Nishid C, Gritli I Kusubata K, Heissig B Hattori K
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2011-10-15
• [Presentation] リンパ腫に対する骨髄由来細胞動員及びマトリックスメタロプロテイナーゼ活性制御を伴うプラスミン阻害剤の有効性 (2011)
  • Author(s): 服部浩一
  • Organizer: 第70回日本癌学会
  • Place of Presentation: 名古屋国際会議場、名古屋市
  • Year and Date: 2011-10-03
• [Presentation] 血液線維素溶解系と臓器・組織再生・最近の知見 (2011)
  • Author(s): 服部浩一
  • Organizer: 第4回臓器保護と治療研究
  • Place of Presentation: 会艮陵会館、仙台市
  • Year and Date: 2011-09-26
  • Invited
• [Remarks]
  • URL: http://stemcell-u-tokyo.org/sc-re/
• [Patent(Industrial Property Rights)] 炎症性疾患治療剤 (2011)
  • Inventor(s): 服部浩一 津田裕子 服部ハイジッヒベアテ
  • Industrial Property Number: COP-04115
  • Filing Date: 2011-09-02
  • Overseas