Roles of angiocrine factor signaling in the pathogenesis of leukemia/lymphoma

• Project/Area Number: 26461415
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: HATTORI KOICHI 順天堂大学, 医学(系)研究科(研究院), 特任先任准教授 (10360116)
• Co-Investigator(Renkei-kenkyūsha): Takahashi Satoshi 東京大学, 医科学研究所・幹細胞治療センター, 准教授 (60226834)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血液腫瘍学 / 血液内科学 / 生体分子 / 細胞・組織 / 血管新生 / 酵素

Outline of Final Research Achievements

Angiocrine factors released from endothelial cells directly can regulate hematopoiesis and leukemia/lymphoma growth. The serine protease tissue type plasminogen activator, a classical fibrinolytic factor, its endogenous inhibitor plasminogen activator inhibitor-1 and its downstream targets matrix metalloproteases can be released from endothelial cells, and therefore also can be regarded as angiocrine factors. We could show that angiocrine factors regulate leukemia/lymphoma growth and control inflammatory diseases, thereby preventing tissue damage, and disease-associated death in murine models of inflammation. Our recent studies demonstrate that pharmacological and genetic control of the fibrinolytic system is a new therapeutic approach to treat inflammation-associated leukemia/lymphoma and associated diseases. Therefore, the initially proposed action plan for this research was performed as proposed and the targets achieved.

Research Products

• [Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome (2017)
  • Author(s): 1.Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonser S, Ohta Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B and Hattori K
  • Journal Title: Blood Volume: 印刷中 Issue: 1 Pages: 59-72
  • DOI: 10.1182/blood-2016-09-738096
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice. (2017)
  • Author(s): Honjo K, Munakata S, Tashiro Y, Salama Y, Shimazu H, Eiamboonsert S, Dhahri D, Ichimura A, Dan T, Miyata T, Takeda K, Sakamoto K, Hattori K, Heissig B.
  • Journal Title: FASEB Journal Volume: - Issue: 6 Pages: 2625-2637
  • DOI: 10.1096/fj.201600871rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 炎症性腸疾患と線溶系 (2017)
  • Author(s): 服部浩一
  • Journal Title: 日本血栓止血学会雑誌 Volume: 印刷中
• [Journal Article] The fibrinolytic pathway expands the murine bone marrow mesenchymal stem/stromal cells through a crosstalk with endothelial cells (2016)
  • Author(s): 3.Dhahri D, Sato-Kusubata K, Ohki-Koizumi M, Nishida C, Tashiro Y, Munakata S, Shimazu H, Salama Y, Eiamboonser S, Nakauchi H, Hattori K and Heissig B
  • Journal Title: Blood Volume: 128 Issue: 8 Pages: 1063-1075
  • DOI: 10.1182/blood-2015-10-673103
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 新着論文 要約と解説 New Arrival & Comments Cox TR, Rumney RM, Schoof EM, et al: The hypoxic cancer secretome inducespre- metastatic bone lesions through lysyl oxidase. Nature 522: 106-110, 2015 (2016)
  • Author(s): 服部浩一
  • Journal Title: Olive-骨代謝病と生活習慣病の連関 Volume: 6 Pages: 29-32
  • Open Access
• [Journal Article] マトリックスメタロプロテイナーゼによるがん転移制御 (2016)
  • Author(s): 服部浩一 本庄薫平
  • Journal Title: 医学のあゆみ Volume: 257 Pages: 1223-1228
  • Acknowledgement Compliant
• [Journal Article] Cancer therapy targeting the fibrinolytic system (2016)
  • Author(s): Heissig B, Eiamboonsert S, Salama Y, Shimazu H, Dhahri D, Munakata S Tashiro Y and Hattori K
  • Journal Title: Advanced Drug Delivery Rev Volume: 印刷中 Pages: 172-179
  • DOI: 10.1016/j.addr.2015.11.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of mesenchymal stem cell-derived factor in tissue regeneration and cancer progression (2015)
  • Author(s): Heissig B, Dhahri D, Eiamboonsert S, Salama Y, Shimazu H, Munakata S and Hattori K
  • Journal Title: Cell Mol Life Sci Volume: 72 Pages: 4759-4770
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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): Sato A,Nishida C,Sato-Kusubata K,Ishihara M,Tashiro Y,Gritli I,Shimazu H, Munakata S,Yagita H,Okumura K,Tsuda Y,Okada Y,Tojyo A,Nakauchi H, Takahashi S,Heissig B and Hattori K
  • Journal Title: Leukemia Volume: 29 Pages: 145-156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 血管ニッチにおけるアンジオクライン因子による幹細胞制御機構 (2015)
  • Author(s): 服部浩一
  • Journal Title: がん微小環境と標的治療 実験医学増刊号 Volume: 33 Pages: 112-117
• [Journal Article] がん増殖における炎症性細胞と微小環境の相互作用 (2015)
  • Author(s): Heissig B, 服部浩一
  • Journal Title: がん微小環境と標的治療 実験医学増刊号 Volume: 33 Pages: 67-72
• [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
• [Presentation] Roles of plasmin for the progression of HPS/MAS in mice (2016)
  • Author(s): Shimazu H. Tashiro Y. Nakauchi H. Heissig B, HattoriK
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] 炎症性腸疾患におけるプロテアーゼの機能解明 (2016)
  • Author(s): 宗像慎也、 植山孝恵、 牧野有里香、 本庄薫平、 青木 順、高橋里奈、丹羽浩一郎、石山隼、 杉本起一、 神山博彦、高橋玄、小見山博光、小島豊、五藤倫敏、冨木裕一、坂本一博、ベアテハイジッヒ、服部 浩一
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2016-04-14
• [Presentation] Roles of fibrinolytic factors for the progression of HPS/MAS (2015)
  • Author(s): Shimazu H. Tashiro Y. Nakauchi H. Heissig B, HattoriK
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢市
  • Year and Date: 2015-10-16
• [Presentation] 腹腔内癒着における線溶系阻害因子PAI-1の機能解明 (2015)
  • Author(s): 宗像慎也 本庄薫平 島津浩 田代良彦 市村敦彦 段孝 宮田敏男 Beate Heissig 服部浩一 坂本一博
  • Organizer: 第70回日本消化器外科学会総会
  • Place of Presentation: 浜松
  • Year and Date: 2015-07-15
• [Presentation] nhibition of plasmin protects against experimental colitis by suppressing the matrix metalloproteinase-9-mediated cytokine release from myeloid cells (2015)
  • Author(s): Munakata S, Tashiro Y, Sakamoto K,Okada Y, Heissig B, Hattori K
  • Organizer: Digestive disease week (DDW)
  • Place of Presentation: Washington,DC, USA
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] 腔内癒着における線溶系阻害因子PAI-1の機能解明 (2015)
  • Author(s): 本庄薫平, 塚本亮一, 植山孝恵, 伊藤慎吾, 市川亮介, 呉一眞, 盧尚志, 田代良彦, 宗像慎也, 高橋玄, 小見山博光, 小島豊, 五藤倫敏, 冨木裕一, 市村敦彦, 段孝, 宮田敏男, Beate Heissig, 服部浩一, 坂本一博
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 愛知県
  • Year and Date: 2015-04-18
• [Presentation] プロテアーゼ活性調節による新規治療法開発の現状とその展望 (2015)
  • Author(s): 服部浩一
  • Organizer: JST.CREST ips細胞領域合同シンポジウム
  • Place of Presentation: 東京フォーラム 東京都
  • Year and Date: 2015-02-23
  • Invited
• [Presentation] Epidermal growth factor-like domain 7 promotes hematopoietic stem cell expansion and increases myeloid-megakaryocytic lineage priming through beta3 integrin (2014)
  • Author(s): Nishida C , Salama Y, Gritli, I, Umemoto T, Nakauchi H, Hattori K, Heissig B
  • Organizer: 第56回アメリカ血液学会
  • Place of Presentation: サンフランシスコ USA
  • Year and Date: 2014-12-07
• [Presentation] Therapeutic targeting of the fibrinolytic system controls TNF-αassociated inflammatory diseases. (2014)
  • Author(s): Hattori K, Munakata S, Sato A, Shimazu H. Tashiro Y. Nishida C. Nakauchi H. Heissig B
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪市
  • Year and Date: 2014-11-02
• [Presentation] Parmacological targeting of plasmin prevents macrophage activation syndrome in mice. (2014)
  • Author(s): Shimazu H, Munakata S, Nishida C, Sato A, Tashiro Y , Sato Y, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪市
  • Year and Date: 2014-11-02
• [Presentation] Plasmin inhibitor regulates cytokine storm and effector cell trafficking by suppressing MMP-9 (2014)
  • Author(s): Sato A, Nishida C, Munakata S, Heissig B, Hattori K
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪市
  • Year and Date: 2014-10-31
• [Presentation] 線維素溶解系（線溶系）による炎症性腸疾患の制御機構の解明 (2014)
  • Author(s): 宗像慎也、田代良彦、島津浩、佐藤亜紀、西田知恵美、小見山博光、坂本一博、Heissig Beate、服部浩一
  • Organizer: 日本消化器関連学会週間
  • Place of Presentation: 神戸国際展示場 神戸市
  • Year and Date: 2014-10-23
• [Presentation] MT1-MMP plays a critical role in chemo-/cytokine expression by regulating HIF activation (2014)
  • Author(s): Nishida C, Heissig B, Hattori K,
  • Organizer: 第18回国際血管生物学会,
  • Place of Presentation: みやこメッセ 京都
  • Year and Date: 2014-04-15
• [Presentation] The fibrinolytic pathway is required for Mesenchimal Stem and Endothelial cell. (2014)
  • Author(s): Heissig B, Dhahri D, Nishida C, Kusubata K, Koizumi M, Hattori K
  • Organizer: The18th International Vasular Biology Meeting
  • Place of Presentation: みやこメッセ 京都市
  • Year and Date: 2014-04-14
• [Presentation] EGFL7 recruits quiescent HSCs into active cell cycle and expands HSCs (2014)
  • Author(s): Nishida C, Salama Y, Hattori K, Heissig B,
  • Organizer: 第18回国際血管生物学会
  • Place of Presentation: みやこメッセ 京都市
  • Year and Date: 2014-04-14
• [Book] 最新の疾患/動物モデルの作成技術と病態解析,開発への応用 (2017)
  • Author(s): 服部 浩一
  • Publisher: 技術情報協会
• [Book] がん微小環境と標的治療 (2015)
  • Author(s): 服部浩一
  • Total Pages: 210
  • Publisher: 羊土社
• [Book] がん微小環境と標的治療 (2015)
  • Author(s): Heissig B,服部浩一
  • Total Pages: 210
  • 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
  • URL: http://stemcell-u-tokyo.org/
• [Remarks] 順天堂大学 News & Information 炎症性腸疾患の新たな病態機序を解明
  • URL: http://www.juntendo.ac.jp/graduate/pdf/news17.pdf
• [Remarks] 東京大学医科学研究所 幹細胞治療研究センター 幹細胞制御領域
  • URL: http://stemcell-u-tokyo.org/sc-re/