Cell adhesion-mediated drug resistance of myeloma cells via Wnt/Rho signaling pathway

• Project/Area Number: 19591124
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Sapporo Medical University
• Principal Investigator: MASAYOSHI Kobune Sapporo Medical University, 医学部, 講師 (90336389)
• Co-Investigator(Kenkyū-buntansha): KATO Junji 札幌医科大学, 医学部, 教授 (20244345)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 骨髄腫 / Wnt / Rhoシグナル / 骨髄間質細胞 / 薬剤耐性

Research Abstract

近年、血液腫瘍に対する化学療法や分子標的療法は目覚ましい進歩をとげたが、骨髄腫や難治性白血病などでは、腫瘍細胞を骨髄から完全に排除することが出来ず、治癒を得ることは困難である。その理由として、骨髄間質と腫瘍細胞の相互作用で惹起される薬剤耐性の関与が想定されているが、その分子機構は明らかとなっていない。本研究ではWntが細胞接着や増殖を制御することに着目し、血液腫瘍におけるWntの発現と抗癌剤耐性への関与を解析した。各種細胞株でのWntの発現を検討した結果、骨髄腫細胞株においてWnt3の発現が検出され、その発現量は骨髄腫細胞のstroma細胞への接着性と相関していた。高接着性の骨髄腫細胞株の共培養でDoxorubicnに対する薬剤耐性は、stroma細胞非存在下に比し有意に上昇したが、抗integrinβ1、Wnt inhibitorあるいはWnt3 siRNAを用いることによって解除された。これらの結果より、骨髄腫において、Wnt3経路はintegrinβ1依存性薬剤耐性を惹起するために重要な役割をしており、新規治療の分子標的になる可能性が示唆された。

Research Products

• [Journal Article] Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab (2009)
  • Author(s): Hirayama Y, Kohda K, Konuma Y, Hirata Y, Kuroda H, Fujimi Y, Shirao S, Kobune M, Takimoto R, Matsunaga T, Kato J
  • Journal Title: Intern Med 48 Pages: 57-60
  • NAID: 130000080003
  • Peer Reviewed
• [Journal Article] Adenoviral vector-mediated transfer of the indian hedgehog gene modulates lymphomyelopoiesis in vivo (2008)
  • Author(s): Kobune M, Kato J, Kawano Y, Sasaki K, Uchida H, Takada K, Takahashi S, Takimoto R, Niitsu Y
  • Journal Title: Stem Cells 26 Pages: 534-542
  • Peer Reviewed
• [Journal Article] Ex vivo large-scale generation of human red blood cells from cord blood CD34(+)cells by co-culturing with macrophages (2008)
  • Author(s): Fujimi A, Matsunaga T, Kobune M, Kawano Y, Nagaya T, Tanaka I, Iyama S, Hayashi T, Sato T, Miyanishi K, Sagawa T, Sato Y, Takimoto R, Takayama T, Kato J, Gasa S, Sakai H, Tsuchida E, Ikebuchi K, Hamada H, Niitsu Y
  • Journal Title: Int J Hematol 87 Pages: 339-350
  • NAID: 10025158459
  • Peer Reviewed
• [Journal Article] Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone (2008)
  • Author(s): Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K, Miyanishi K, Matsunaga T, Takayama T, Niitsu Y
  • Journal Title: Nat Biotechnol 26 Pages: 431-442
  • Peer Reviewed
• [Journal Article] Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin-CD34-cells (2008)
  • Author(s): Kobune M, Kawano Y, Takahashi S, Takada K, Murase K, Iyama S, Sato T, Takimoto R, Niitsu Y, Kato J
  • Journal Title: Exp Hematol 36 Pages: 1121-1131
  • Peer Reviewed
• [Journal Article] Apoptosis supercedes necrosis in mitochondrial DNA-depleted Jurkat cells by cleavage of receptorinteracting protein and inhibition of lysosomal cathepsin (2008)
  • Author(s): Sato T, Machida T, Takahashi S, Murase K, Kawano Y, Hayashi T, Iyama S, Takada K, Kuribayashi K, Sato Y, Kobune M, Takimoto R, Matsunaga T, Kato J, Niitsu Y
  • Journal Title: J Immunol 181 Pages: 197-207
  • Peer Reviewed
• [Journal Article] Successful treatment of chronic myeloproliferative diseaseunclassifiable(CMPD-U)with no chromosomal abnormalities by imatinib mesylate (2008)
  • Author(s): Iyama S, Matsunaga T, Sato T, Murase K, Araki N, Takimoto R, Kobune M, Sagawa T, Takayama T, Niitsu Y
  • Journal Title: Intern Med 47 Pages: 791-794
  • Peer Reviewed
• [Journal Article] Successful treatment of autoimmune pancreatitis complicated with autoimmune thrombocytopenia and interstitial pneumonia by prednisolone (2008)
  • Author(s): Murase K, Matsunaga T, Hayashi T, Ishiwatari H, Araki N, Iyama S, Sato T, Kobune M, Takimoto R, Miyanishi K, Miyazaki T, Ikeda H, Kato J, Niitsu Y
  • Journal Title: Intern Med 47 Pages: 1033-1038
  • NAID: 130000078663
  • Peer Reviewed
• [Journal Article] Adenoviral vector-mediated transfer of the indian hedgehog gene modulates lymphomyelopoiesis in vivo (2008)
  • Author(s): Kobune-M, et al.
  • Journal Title: Stem Cells 26 Pages: 534-542
  • Peer Reviewed
• [Journal Article] Ex vivo large-scale generation of human red blood cells from cord blood CD34+ cells by co-culturing with macrophages (2008)
  • Author(s): Fujimi-A, et al.
  • Journal Title: Int J Hematol 87 Pages: 339-350
  • Peer Reviewed
• [Journal Article] Resolution of liver cirrhosis using vitamine A-coupled liposomes to deliver siRNA against a collagen-specific chaperone (2008)
  • Author(s): Kobune-M, et al. (12中4番目)
  • Journal Title: Nat Biotechnol 26 Pages: 431-442
  • Peer Reviewed
• [Journal Article] Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin-CD34- cells (2008)
  • Author(s): Kobune-M, et al.
  • Journal Title: Exp Hematol 36 Pages: 1121-1131
  • Peer Reviewed
• [Journal Article] Apoptosis supercedes necrosis in mitochondrial DNA-depleted Jurkat cells by cleavage of receptor-interacting protein and inhibition of lysosomal cathepsin (2008)
  • Author(s): Kobune-M, et al. (11中14番目)
  • Journal Title: J Immunol 181 Pages: 197-207
  • Peer Reviewed
• [Journal Article] Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism (2007)
  • Author(s): Kobune M, Chiba H, Kato J, Kato K, Nakamura K, Kawano Y, Takada K, Takimoto R, Takayama T, Hamada H, Niitsu-Y
  • Journal Title: Mol Cancer Ther 6 Pages: 1774-1784
  • Peer Reviewed
• [Journal Article] Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation (2007)
  • Author(s): Kato J, Kobune M, Ohkubo S, Fujikawa K, Tanaka M, Takimoto R, Takada K, Takahari D, Kawano Y, Kohgo Y, Niitsu Y
  • Journal Title: Exp Hematol 35 Pages: 879-887
  • Peer Reviewed
• [Journal Article] Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. (2007)
  • Author(s): Kobune M, et. al.
  • Journal Title: Molecular Cancer Therapeutics 6 Pages: 1774-1784
  • Peer Reviewed
• [Journal Article] Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation. (2007)
  • Author(s): Kato J, et. al.
  • Journal Title: Experimental hematology 35 Pages: 879-887
  • Peer Reviewed
• [Journal Article] Adenoviral Vector-Mediated Transfer of the Indian Hedgehog Gene Modulates Lymphomyelopoiesis in vivo. (2007)
  • Author(s): Kobune M, et. al.
  • Journal Title: Stem Cells 26 Pages: 534-542
  • Peer Reviewed
• [Presentation] Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin-CD34-cells via Wnt signaling (2008)
  • Author(s): Kobune M, Murase K, Iyama S, Sato T, Kikuchi S, Kawano Y, Takada K, Miyanishi K, Takimoto R, Kato J
  • Organizer: In : The 50th Annual Meeting of American Society of Hematology(Blood 2008 ; 112 : 2325a)
  • Place of Presentation: San Francisco, U.S.A.
• [Presentation] Hedgehog inhibitors reduce the survival and drug resistance in CD34+ leukemic cells (2008)
  • Author(s): Kobune M, Murase K, Iyama S, Sato T, Takimoto R, Kikuchi S, Kawano Y, Takada K, Miyanishi K, Kato J
  • Organizer: In : The 50th Annual Meeting of American Society of Hematology(Blood 2008 ; 112 : 1611a)
  • Place of Presentation: San Francisco, U.S.A.
• [Presentation] Wnt3 signaling augments integrinβ1-dependent adhesion-mediated drug resistance of multiple myeloma in autocrine and paracrine manner (2008)
  • Author(s): Kobune M, Murase K, Iyama S, Sato T, Takimoto R, Kawano Y, Kikuchi S, Takada K, Miyanishi K, Sato Y, Kato J
  • Organizer: In : The 50th Annual Meeting of American Society of Hematology(Blood 2008 ; 112 : 1698a)
  • Place of Presentation: San Francisco, U.S.A.
• [Presentation] Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin-CD34-cells via Wnt signaling (2008)
  • Author(s): Kobune-M, et al.
  • Organizer: The 50th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Francisco, U. S. A
• [Presentation] Hedgehog inhibitors reduce the survival and drug resistance in CD34+ leukemic cells (2008)
  • Author(s): Kobune-M, et al.
  • Organizer: The 50th Annual Meet ing of American Society of Hematology
  • Place of Presentation: San Francisco, U. S. A
• [Presentation] Wnt3 signaling augments integrinβ1-dependent adhesion-mediated drug resistance of multiple myeloma in autocrine and paracrine manner (2008)
  • Author(s): Kobune-M, et al.
  • Organizer: The 50th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Francisco, U. S. A
• [Presentation] Wnt3/RhoA/ROCK signaling pathway is involved in VLA6-dependent adhesion-mediated drug resistance of multiple myeloma. (2007)
  • Author(s): Kobune M, et. al.
  • Organizer: The 49th Annual Meeting of American Society of Hematology : 2007
  • Place of Presentation: Atranta, U.S.A.
• [Book] 貧血治療指針2008. IIIエビデンスからみた鉄剤適正使用のための指針-鉄の生理作用と過剰鉄による臓器障害 (2009)
  • Author(s): 加藤淳二, 小船雅義
  • Publisher: 札幌 : 響文社
• [Book] 血液疾患アプローチのための解剖生理 [病気と薬パーフェクトガイド3 月増刊号 病気と薬パーフェクトBOOK 2008 (2008)
  • Author(s): 小船雅義、加藤淳二
  • Publisher: 東京 : 南山堂
• [Book] 血液疾患アプローチのための解剖生理 [病気と薬パーフェクトガイド3月増刊号 病気と薬パーフェクトBOOK 2008 (2008)
  • Author(s): 小船雅義ら
  • Total Pages: 4
  • Publisher: 南山堂
• [Book] 第1章4鉄代謝の病態生理, フェリチン. 堀田知光、押味和夫監修. Iron Overload鉄キレート療法 (2007)
  • Author(s): 小船雅義, 加藤淳二, 新津洋司郎
  • Publisher: 東京 : メディカルレビュー社
• [Book] 第2章1鉄過剰症の病態と診断, 総論. 堀田知光、押味和夫監修. Iron Overload鉄キレート療法 (2007)
  • Author(s): 小船雅義, 新津洋司郎
  • Publisher: 東京 : メディカルレビュー社