Establishment of in vivo model for angiogenesis in hematological malignancy and development of anti-angiogenic therapy.

• Project/Area Number: 17590318
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: KEIO UNIVERSITY
• Principal Investigator: YAMADA Taketo Keio University, School of Medicine, Instructor, 医学部, 講師 (60230463)
• Co-Investigator(Kenkyū-buntansha): HOZUMI Nobumichi Science University of Tokyo, Institute of Biological Sciences, Professor, 生命科学研究所, 教授 (60051744) ; 杜 ぶん林 慶應義塾大学, 医学部, 助手 (90348798)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: Cacer / Pathology / leukemia / Angiogenesis / Cell・Tissue / 癌 / 免疫学

Research Abstract

Angiogenesis plays a critical role in solid tumor development, invasion and metastasis. Recently, a role of angiogenesis in the pathology of leukemia and multiple myeloma has been suggested. The purpose of this work was to generate a model for human leukemia with human angiogenesis and then to study the meaning of angiogenesis in human leukemias. Human cancellous bones, which were irradiated (8 Gy), were transplanted into subcutaneous tissue of NOD/SCID mice (hu-Bone mice). Human microvessels were observed in not only the transplanted bone marrow and bone but also around murine subcutaneous tissues over six months. Human leukemic Raji cells were inoculated into these hu-bone mice. The leukemic cells invaded diffusely into the transplanted human bone marrow within 14 days after innoculation, several days later into murine bone marrow and around the spinal cord. The density of microvessels in human bone narrow with the leukemic infiltration elevated significantly as compared to one of hu -bone mice which were inoculated with normal human bone marrow cells or with saline only. The increased density of microvessels associated with leukemic invasion was independent in age or sex of bone donors. The mRNA of vascular endothelial growth factor(VEGF)121,165, angiopoietin-1,2 and angiopoietin-like factor were detected in cultured Raji cells using RT-PCR. Soluble TIE2-Fc chimeric protein inhibited the development of invasion of leukemic cells and angiogenesis. Futhermore the expression of phosphatidylinositol-3 Kinase(p85a) in endothelia of bone marrow which involved with leykemic cells was augmented. The inhibition of p85a signalling resulted impairments of angiogenesis in bone marrow. The gene transfer of dominant negative forms of receptors for Flt-1,FGF and Eph using a tricystronic vector into leukemic cells was done and the alteration of leukamic invasiveness is examined. These observation suggested the angiogenesis in bone marrow by human leukemic infiltration was induced via certain angiogenetic factors produced by leukemic cells. This model for human leukemia with human angiogenesis may be useful for to search novel therapies or to do preclinical tests of drugs.

Research Products

• [Journal Article] NK4 an Antagonist of Hepatocyte Growth Factor (HGF), Inhibits Growth of Multip Myeloma Cells in Vivo; Molecular Targeting of Angiogenic Growth Factor (2007)
  • Author(s): Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, Otsuki T, Niikur T, Nukiwa T, Ikeda Y
  • Journal Title: Blood 109 (7) Pages: 3042-3049
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] NK4, an Antagonist of Hepatocyte Growth Factor (HGF), Inhibits Growth of Multiple Myeloma Cells in Vivo ; Molecular Targeting of Angiogenic Growth Factor (2007)
  • Author(s): Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, Otsuki T, Niikura T, Nukiwa T, Ikeda Y
  • Journal Title: Blood 109(7) Pages: 3042-3049
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NK4, an Antagonist of Hepatocyte Growth Factor (HGF), Inhibits Growth of Multip Myelome Cells in Vivo; Molecular Targeting of Angiogenic Growth Factor (2007)
  • Author(s): Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, Otsuki T, Niikur T, Nukiwa T, Ikeda Y
  • Journal Title: Blood 109(7) Pages: 3042-3049
• [Journal Article] Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferalive disorder with hemophagocytosis following autologous peripheral blood stem ce transplantation for relapsed angioimmuunoblastic T-cell lymphoma (2006)
  • Author(s): Awaya N, Adachi A, Mori T, Kamata H, Nakahara J, Yokoyama K, Yamada T, Kizak M, Sakamoto M, Ikeda Y, Okamoto S
  • Journal Title: Leukemia Research 30(8) Pages: 1059-1062
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. (2006)
  • Author(s): Ohteki T, Tada H, Ishida K, Sato T, Mak C, Yamada T, Hamuro J, Koyasu S
  • Journal Title: J Exp Med 203(10) Pages: 2329-2338
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem cell transplantation for relapsed angioimmunoblastic T-cell lymphoma (2006)
  • Author(s): Awaya N, Adachi A, Mori T, Kamata H, Nakahara J, Yokoyama K, Yamada T, Kizaki M, Sakamoto M, Ikeda Y, Okamoto S
  • Journal Title: Leukemia Research 30(8) Pages: 1059-1062
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. (2006)
  • Author(s): Ohteki T, Tada H, Ishida K, Sato T, Maki C, Yamada T, Hamuro J, Koyasu S
  • Journal Title: J Exp Med 203(10) Pages: 2329-2338
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem ce transplantation for relapsed angioimmunoblastic T-cell lymphoma (2006)
  • Author(s): Awaya N, Adachi A, Mori T, Kamata H, Nakahara J, Yokoyama K, Yamada T, Kizak M, Sakamoto M, Ikeda Y, Okamoto S
  • Journal Title: Leukemia Research 30(8) Pages: 1059-1062
• [Journal Article] Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. (2006)
  • Author(s): Ohteki T, Tada H, Ishida K, Sato T, Mak C, Yamada T, Hamuro J, Koyasu S.
  • Journal Title: J Exp Med 203(10) Pages: 2329-2338
• [Journal Article] Establishment of Perineural Invasion Models and Analysis of Gene Expression Revealed an Invariant Chain (CD74) as a Possible Molecule involved in Perineura Invasion in Pancreatic Cancer (2006)
  • Author(s): Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimaz M, Hirohashi S, Nimura Y, Sakamoto M
  • Journal Title: Clin Cancer Res 12(8) Pages: 2419-2426
• [Journal Article] Induction of cell death in human papillomavirus 18-positive cervical cancer cell by E6 siRNA. (2006)
  • Author(s): Yamato K, Fen J, Kobuchi H, Nasu Y, Yamada T, Nishihara T, Ikeda Y, Kizak M, Yoshinouchi M
  • Journal Title: Cancer Gene Therapy 13(3) Pages: 234-241
• [Journal Article] Catechin, a green tea component, rapidly induces apoptosis of myeloid leukem cells via modulation of reactive oxygen species (ROS) production in vitro an inhibits tumor growth in vivo. (2005)
  • Author(s): Nakazato T, Ito K, Miyakawa Y, Kinjo K, Yamada T, Hozumi N, Ikeda Y, Kizaki M
  • Journal Title: Hematologica 90(3) Pages: 317-325
• [Journal Article] Expression of Cre recombinase in the mouse developing chondrocytes driven by th mouse a2(XI) collagen promoter. (2005)
  • Author(s): Fujimaki R, Hayashi K, Watanabe N, Yamada T, Toyama Y, Tezuka K, Hozumi
  • Journal Title: J Bone and Mineral Metabolism 23(3) Pages: 270-273
• [Journal Article] 1'-acetoxychavicol acetate is a novel muclear factor-kB inhibitor with significant activity against multiple myeloma in vitro and in vivo. (2005)
  • Author(s): Ito K, Nakazato T, Xian MJ, Yamada T, Hozumi N, Murakami A, Ohigashi H, Ikeda Y, Kizaki M
  • Journal Title: Cancer Research 65(10) Pages: 4417-4424
• [Journal Article] Primary bone carcinosarcoma : Chondrosarcoma and squamous cell carcinoma with keratin pearl formation. (2005)
  • Author(s): Shiraishi J, Mukai M, Yabe H, Shibata R, Yamada T, Miura K, Anazawa U, Morioka H, Sakamoto M
  • Journal Title: Pathology International 55(8) Pages: 504-509
  • NAID: 10019344809