Development of gene therapy for malignant lymphoma using mesenchymal stem cells with tumor-accumulating capacity

• Project/Area Number: 19390267
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: OZAWA Keiya Jichi Medical University, 医学部, 教授 (30137707)
• Co-Investigator(Kenkyū-buntansha): OZAKI Katsutoshi 自治医科大学, 医学部, 講師 (10286453)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2008: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 悪性リンパ腫 / 間葉系幹細胞 / 腫瘍集積性 / 遺伝子治療 / 抗腫瘍性サイトカイン / 遺伝子導入 / 細胞治療 / 可溶型TRAIL

Research Abstract

(1)間葉系幹細胞(MSC: mesenchymal stem cell)の腫瘍集積性を応用した悪性リンパ腫に対する新規治療法の開発研究を行った。可溶型TRAIL の腫瘍細胞に対するアポトーシス誘導を利用した治療ストラテジーの有用性を見出した。
(2)MSC の腫瘍集積性を増強するために、腫瘍集積性の分子機構に関する検討を行った。TNF-αによる接着分子の発現誘導、ならびに血管内皮細胞への接着性の亢進がMSC の腫瘍集積性に重要な役割を担っていることを明らかにした。

Research Products

• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. (2009)
  • Author(s): Uchibori, R., Okada, T., Ito, T., Urabe, M., Mizukami, H., Kume, A., and Ozawa, K.
  • Journal Title: J. Gene Med. 11 Pages: 373-381
  • Peer Reviewed
• [Journal Article] Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. (2009)
  • Author(s): Hatano, K., Kikuchi, J., Takatoku, M., Shimizu, R., Wada, T., Ueda, M., Nobuyoshi, M., Oh, I., Sato, K., Suzuki, T., Ozaki, K., Mori, M., Nagai, T., Muroi, K., Kano, Y,. Furukawa, Y., and Ozawa, K.
  • Journal Title: Oncogene 28(2) Pages: 231-242
  • Peer Reviewed
• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. (2009)
  • Author(s): Uchibori, R.
  • Journal Title: J. Gene Med. 11 Pages: 373-381
  • Peer Reviewed
• [Journal Article] Bortezomib overcomes cell adhesion-mediated drug resistance through dovvnregulation of VLA-4 expression in multiple myeloma. (2009)
  • Author(s): Hatano, K.
  • Journal Title: Oncogene 28 Pages: 231-242
  • Peer Reviewed
• [Journal Article] High-resolution analysis of chromosome copy number alterations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified, with single nucleotide polymorphism-typing microarrays. (2008)
  • Author(s): Fujiwara, S., Yamashita, Y., Nakamura, N., Choi, Y.L., Ueno, T., Watanabe, H., Kurashina, K., Soda, M., Enomoto, M., Hatanaka, H., Takada, S., Abe, M., Ozawa, K., and Mano, H.
  • Journal Title: Leukemia 22(10) Pages: 1891-1898
  • Peer Reviewed
• [Journal Article] Thrombopoietin (TPO) regulates HIF-1alpha levels through generation of mitochondrial reactive oxygen species. (2008)
  • Author(s): Yoshida, K., Kirito, K., Yongzhen, H., Ozawa, K., Kaushansky, K., and Komatsu, N.
  • Journal Title: Int J Hematol. 88(1) Pages: 43-51
  • Peer Reviewed
• [Journal Article] Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. J. Cell. (2008)
  • Author(s): Nagai, T., Kikuchi, S., Ohmine, K., Miyoshi, T., Nakamura, M., Kondo, T., Furuyama, K., Komatsu, N., and Ozawa, K.
  • Journal Title: Biochem. 104(2) Pages: 680-691
  • Peer Reviewed
• [Journal Article] Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats. (2008)
  • Author(s): Nonaka-Sarukawa, M., Okada, T., Ito, T., Yamamoto, K., Yoshioka, T., Nomoto, T., Hojo, Y., Shimpo, M., Urabe, M., Mizukami, H., Kume, A., Ikeda, U., Shimada, K., and Ozawa, K.
  • Journal Title: J Gene Med. 10(4) Pages: 368-374
  • Peer Reviewed
• [Journal Article] Cell and gene therapy using mesenchymal stem cells (MSCs). (2008)
  • Author(s): Ozawa, K., Sato, K., Oh, I., Ozaki, K., Uchibori, R., Obara, Y., Kikuchi, Y., Ito, T., Okada, T., Urabe, M., Mizukami, H., and Kume, A.
  • Journal Title: J. Autoimmun. 30(3) Pages: 121-127
• [Journal Article] Vector-producing tumor-tracking multipotent mesenchymal stromal cells for suicide cancer gene therapy. Front. (2008)
  • Author(s): Okada, T. and Ozawa, K.
  • Journal Title: Biosci. 13 Pages: 1887-1891
• [Journal Article] Cell and gene therapy using mesenchymal stem cells (MSCs). (2008)
  • Author(s): Ozawa, K., Sato, K., Oh, I., Ozaki, K,. Uchibori, R., Obara, Y., Kikuchi, Y., Ito, T.,Okada, T., Urabe, M., Mizukami, H., and Kume, A.
  • Journal Title: J. Autoimmun. 30(3) Pages: 121-127
• [Journal Article] Vectorproducing tumor-tracking multipotent mesenchymal stromal cells for suicide cancer gene therapy. (2008)
  • Author(s): Okada, T. and Ozawa, K.
  • Journal Title: Front. Biosci. 13 Pages: 1887-1891
  • Peer Reviewed
• [Journal Article] High-resolution analysis of chromosome copy number alterations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified, with single nucleotide polymorphism-typing microarrays. (2008)
  • Author(s): Fujiwara, S.
  • Journal Title: Leukemia 22 Pages: 1891-1898
  • Peer Reviewed
• [Journal Article] Thrombopoietin (TPO)regulates HIF-lalpha levels through generation of mitochondrial reactive oxygen species. (2008)
  • Author(s): Yoshida, K.
  • Journal Title: Int J Hematol. 88 Pages: 43-51
  • Peer Reviewed
• [Journal Article] Hemin reduces cellular sensitivity to itnatinib and anthracyclins via Nrf2. (2008)
  • Author(s): Nagai, T.
  • Journal Title: J. Cell. Biochem. 104 Pages: 680-691
  • Peer Reviewed
• [Journal Article] Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats. (2008)
  • Author(s): Nonaka-Sarukavva, M.
  • Journal Title: J Gene Med. 10 Pages: 368-374
  • Peer Reviewed
• [Journal Article] Cell and gene therapy using mesenchymal stem cells (MSCs). (2008)
  • Author(s): Ozawa, K.
  • Journal Title: J. Autoimmun. 30 Pages: 121-127
• [Journal Article] Vector-producing tumor-tracking multipotent mesenchymal stromal cellsfor suicide cancer gene therapy. (2008)
  • Author(s): Okada, T.
  • Journal Title: Front. Biosci. 13 Pages: 1887-1891
• [Journal Article] Cell and gene therapy using mesenchymal stem cells(MSCs). (2008)
  • Author(s): Ozawa, K.
  • Journal Title: J.Autoimmun. 30 Pages: 121-127
• [Journal Article] Vector-producing tumor-tracking multipotent mesenchymal stromal cells for suicide cancer gene therapy. (2008)
  • Author(s): Okada, T.
  • Journal Title: Front. Biosci. 13 Pages: 1887-1891
• [Journal Article] Mechanisms of immunomodulation by mesenchymal stem cells. (2007)
  • Author(s): Ozaki, K., Sato, K., Oh, I., Meguro, A., Tatara, R., Muroi, K., and Ozawa, K.
  • Journal Title: Int. J. Hematol. 86 Pages: 5-7
  • NAID: 10018515331
  • Peer Reviewed
• [Journal Article] Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosisinducing ligand. (2007)
  • Author(s): Kikuchi, S., Nagai, T., Kunitama, M., Kirito, K., Ozawa, K., and Komatsu, N.
  • Journal Title: Cancer Sci. 98 Pages: 1949-1958
  • Peer Reviewed
• [Journal Article] Cloning and characterization of a human BCR/ABL-positive cell line, K562/RR, resistant to the farnesyltransferase nhibition by tipifarnib. (2007)
  • Author(s): Miyoshi, T., Nagai, T., Kikuchi, S., Ohmine, K., Nakamura, M., Hanafusa, T., Komatsu, N., and Ozawa, K.
  • Journal Title: Exp. Hematol. 35 Pages: 1358-1365
  • Peer Reviewed
• [Journal Article] Screening of genes responsible for differentiation of mouse mesenchymal stromal cells by DNA microarray analysis of C3H10T1/2 and C3H10T1/2 -derived cell lines. (2007)
  • Author(s): Oh, I., Ozaki, K., Miyazato, A., Sato, K., Meguro, A., Muroi, K., N agai, T., Mano, H., and Ozawa, K.
  • Journal Title: Cytotherapy 9 Pages: 80-90
  • Peer Reviewed
• [Journal Article] Interferon-gamma and NF-kappaB mediate nitric oxide production by mesenchymal stromal cells. (2007)
  • Author(s): Oh, T., Ozaki, K., Sato, K., Meguro, A., Tatara, R., Hatanaka, K., Nagai, T., Muroi, K., Ozawa, K.
  • Journal Title: Biochem. Biophys. Res. Commun. 355 Pages: 956-962
  • Peer Reviewed
• [Journal Article] E2F-6 suppresses growth-associated apoptosis of human hematopoieticprogenitor cells by counteracting proapoptotic activity of E2F-1. (2007)
  • Author(s): Kikuchi, J., Shimizu, R., Wada, T., Ando, H., Nakamura, M., Ozawa, K., and Furukawa, Y.
  • Journal Title: Stem Cells 25 Pages: 2439-2447
  • Peer Reviewed
• [Journal Article] Mechanisms of immunomodulation by mesenchymal stem cells. (2007)
  • Author(s): Ozaki, K.
  • Journal Title: Int. J. Hematol. 86 Pages: 5-7
  • NAID: 40015594590
• [Journal Article] Active FKHRLI overcomes imatinib resistance in chronic myeloaenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligand. (2007)
  • Author(s): Kikuchi, S.
  • Journal Title: Cancer Sci. 98 Pages: 1949-1958
  • Peer Reviewed
• [Journal Article] Cloningand characterization of a human BCR/ABL-positivecell line,K562/RR,resistant to the farnesyltransferase inhibition by tipifarnib. (2007)
  • Author(s): Miyoshi, T.
  • Journal Title: Exp. Hematol. 35 Pages: 1358-1365
  • Peer Reviewed
• [Journal Article] Screening of genes responsible for differentiation ofmouse mesenchymal stromal cells by DNA microarray analysis of C3HIOT 1/2 and C3H10T1/2-derived cell lines. (2007)
  • Author(s): Oh, I.
  • Journal Title: Cytotherapy 9 Pages: 80-90
  • Peer Reviewed
• [Journal Article] Interferon-gamma and NF-kappaB mediate nitric oxide production by mesenchymal stromal cells. (2007)
  • Author(s): Oh, I.
  • Journal Title: Biochem. Biophys. Res. Commun. 355 Pages: 956-962
  • Peer Reviewed
• [Journal Article] E2F-6 suppresses growth-associated apoptosis of human hematopoieticprogenitor cells by counteracting proapoptotic activity of E2F-1. (2007)
  • Author(s): Kikuchi, J.
  • Journal Title: Stem Cells 25 Pages: 2439-2447
  • Peer Reviewed
• [Presentation] Co-transplantation of MSC Improves the Engraftment of HSC after Auto-iBMT in Non-Human Primates. (2008)
  • Author(s): Masuda, S. et al.
  • Organizer: The American Society of Hematology 50^<th> Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-07
• [Presentation] Co-transplantation of MSC Improves the Engraftment of HSC after Auto-iBMT in Non-Human Primates. . (2008)
  • Author(s): Masuda, S.
  • Organizer: The American Society of Hematology 50^<th> Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-07
• [Presentation] Bortezomib Overcomes Cell Adhesion-Mediated Drug Resistance Via Down-regulation of VLA-4 Expression in Multiple Myeloma. (2008)
  • Author(s): Hatano, K. et al.
  • Organizer: The American Society of Hematology 50^<th> Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] Blocking of IL-21 Signal Attenuates Graft-Versus-Host disease but Not Graft-Versus-Leukemia Effect in a Mouse model. (2008)
  • Author(s): Megro, A. et al.
  • Organizer: The American Society of Hematology 50^<th> Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] Blocking of IL-21 Signal Attenuates Graft-Versus-Host disease but Not Graft-Versus-Leukemia Effect in a Mouse model. (2008)
  • Author(s): Megro, A.
  • Organizer: The American Society of Hematology 50^th Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] 間葉系幹細胞と造血幹細胞の相互作用の分子メカニズム (2008)
  • Author(s): 菊池 裕二、他
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] 多発性骨髄腫と骨髄ストローマ細胞間相互作用が誘導する薬剤耐性における鍵分子の探索 (2008)
  • Author(s): 畑野 かおる、他
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] 間葉系幹細胞の腫瘍集積メカニズムにおける炎症性サイトカインの役割 (2008)
  • Author(s): 内堀 亮介、他
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] GVHDにおけるIL-21の役割 (2008)
  • Author(s): 目黒 明子、他
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] AAVを利用した第19番染色体AAVS1領域特異的遺伝子組込み法:遺伝子導入の発現期間に関する検討 (2008)
  • Author(s): 小原 陽子、他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] AAVを利用した第19番染色体AAVSI領域特異的遺伝子組込み法:遺伝子導入の発現期間に関する検討 (2008)
  • Author(s): 小原 陽子
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] 間葉系幹細胞と造血幹細胞の相互作用の分子メカニズム (2008)
  • Author(s): 菊池 裕二、他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] 問葉系幹細胞と造血幹細胞の相互作用の分子メカニズム (2008)
  • Author(s): 菊池 裕二
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] Unexpected silencing of transgene integrated at AAVS1 locus using AAV machinery. (2008)
  • Author(s): Obara, Y. et al.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-13
• [Presentation] 骨髄間葉系幹細胞を用いた細胞治療/遺伝子治療の開発 (2008)
  • Author(s): 小澤 敬也
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-14
• [Presentation] Molecular Mechanisms of Immunosuppressive Activity of MSCs (Mesenchymal Stem Cells) (2008)
  • Author(s): Ozawa, K.
  • Organizer: 第30回日本造血細胞移植学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2008-02-29
• [Presentation] Molecular Mechanisms of Immunosuppressive Activity of MSCs(Mesenchymal Stem Cells) (2008)
  • Author(s): Ozawa, K.
  • Organizer: 第30回日本造血細胞移植学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2008-02-29
• [Presentation] Hyaluronidase and IFN-g from Activated T-cells are Key Mediators to Induce Immunosuppressive Activity of Mesenchymal Stem Cells. (2007)
  • Author(s): Sato, K. et al.
  • Organizer: The American Society of Hematology 49th Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-10
• [Presentation] Hyalumnidase and IFN-g ffom Activated T-cells are Key Medlators to Induce Immunosunnressive Actwity ofMesenchvmal Stem Cells. (2007)
  • Author(s): Sato, K.
  • Organizer: The American Society of Hematology 49^<th> Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-10
• [Presentation] Retroviral vector-producing mesenchymal stem cells for tumor tracking and therapeutic gene amplification in suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R. et al.
  • Organizer: The American Society of Hematology 49th Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] Retroviral vector-producing mesenchymal stem cells for tumor tracking and therapeutic gene amplification in suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R.
  • Organizer: The American Society ofHematology 49^<th> Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] 間葉系幹細胞におけるヒアルロン酸の役割 (2007)
  • Author(s): 佐藤 一也、他
  • Organizer: 日本血液学会日本臨床血液学会合同総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-12
• [Presentation] 間葉系幹細胞におけるピアルロン酸の役割 (2007)
  • Author(s): 佐藤 一也
  • Organizer: 日本血液学会日本臨床血液学会合同総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-12
• [Presentation] ベクター産生型間葉系幹細胞の開発と自殺遺伝子療法への応用 (2007)
  • Author(s): 内堀 亮介、他
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Tumor tracking and therapeutic gene amplification by using retroviral vector-producing Mesenchymal stem cells for reinforcement of suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R. et al.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Nagoya
  • Year and Date: 2007-06-30
• [Presentation] Tumor tracking and therapeutic gene amplification by using retroviral vector-producing Mesenchymal stem cells for reinforcement of suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R.
  • Organizer: The 13^<th> Annual Meeting ofJapan Society ofGene Therapy
  • Place of Presentation: Nagoya
  • Year and Date: 2007-06-30
• [Presentation] MSC (mesenchymal stem cell)-based cell and gene therapy. (2007)
  • Author(s): Ozawa, K. et al.
  • Organizer: 13th ISCT (International Society for Cellular Therapy) Annual Meeting
  • Place of Presentation: Sydney
  • Year and Date: 2007-06-26
• [Presentation] MSC(mesenchymal stem cell)-based cell and gene therapy (2007)
  • Author(s): Ozawa, K.
  • Organizer: 13^<th> ISCT(lnternational Society for Cellular Therapy)Annual Meeting
  • Place of Presentation: Sydney
  • Year and Date: 2007-06-26
• [Presentation] Retroviral vector-producing mesenchymal stem cells for tumor tracking and therapeutic gene amplification as systemic suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R. et al.
  • Organizer: The 10th Annual Meeting of American Society of Gene Therapy
  • Place of Presentation: Seattle
  • Year and Date: 2007-06-02
• [Presentation] Retroviral vector-producing mesenchymal stem cells for tumor tracking and therapeutic gene amplification as systemic suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R.
  • Organizer: The 10^<th> Annual Meeting of American Society ofGene Therapy
  • Place of Presentation: Seattle
  • Year and Date: 2007-06-02
• [Book] Progress in Gene Therapy, Vol. 2, Autologous and Cancer Stem Cell Gene Therapy. (2008)
  • Author(s): Urabe, M. et al.
  • Publisher: World Scientific Publishing Co.