Signaling for regulating hematogenous metastasis of tumors

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014034
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kanazawa University
• Principal Investigator: TAKUWA Yoh Kanazawa University, 医学系, 教授 (60171592)
• Co-Investigator(Kenkyū-buntansha): OKAMOTO Yasuo 金沢大学, 医学系, 准教授 (80293877) ; YOSHIOKA Kazuaki 金沢大学, 医学系, 助手 (80333368)
• Co-Investigator(Renkei-kenkyūsha): SUGIMOTO Naotoshi 金沢大学, 医学系, 准教授 (80272954) ; TAKUWA Noriko 石川県立看護大学, 看護学部, 教授 (70150290)
• Project Period (FY): 2005 – 2009
• Keywords: がん / 血管新生 / スフィンゴシン-1-リン酸 / S1P_2 / 血管成熟

Research Abstract

The lysophospholipid mediator sphingosine-1-phosphate (S1P) exerts positive or negative effects on cell migration and invasion via a receptor family. Among these, the S1P receptor type 2, S1P_2, was found to be expressed in vascular endothelial cells, smooth muscle cells, and bone marrow-derived cells. S1P_2 in the host cells suppresses tumor angiogenesis and tumor growth. On the contrary to previous reports, overexpression of the S1P synthesizing enzyme sphingosine kinase-1 in tumor cells or host tissues does not aggravate tumor progression. S1P_2 in tumor cells and host cells are a potential novel therapeutic target for tumors.

Research Products

• [Journal Article] Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice. (2010)
  • Author(s): X Qi, Y Okamoto, T Murakawa, F Wang, O Oyama, R Ohkawa, K Yoshioka, W Du, N Sugimoto, Y Yatomi, N Takuwa, Y Takuwa
  • Journal Title: Eur J Pharmacol 634 Pages: 121-131
  • Peer Reviewed
• [Journal Article] Y Takuwa S1P2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis and tumor growth in vivo in mice. (2010)
  • Author(s): W Du, N Takuwa, K Yoshioka, Y Okamoto, K Gonda, K Sugihara, A Fukamizu, M Asano
  • Journal Title: Cancer Res 70(2) Pages: 772-781
  • Peer Reviewed
• [Journal Article] JI. Hamada Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with survival of patients with glioblastoma. (2010)
  • Author(s): Y. Yoshida, M. Nakada, N. Sugimoto, T. Harada, Y. Hayashi, D. Kita, N. Uchiyama, Y. Hayashi, A. Yachie, Y. Takuwa
  • Journal Title: Int J Cancer 126(10) Pages: 2341-2352
  • Peer Reviewed
• [Journal Article] S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. (2010)
  • Author(s): N. Takuwa, S. Ohkura, S. Takashima, K. Ohtani, Y. Okamoto, T. Tanaka, K, Hirano, S. Usui, F. Wang, W. Du, K. Yoshioka, Y. Banno, M. Sasaki, I. Ichi, M. Okamura, N. Sugimoto, K. Mizugishi, Y. Nakanuma, I. Ishii, M. Takamura, S. Kaneko, S. Kojo, K. Satouchi, K. Mitumori, J. Chun, Y. Takuwa
  • Journal Title: Cardiovasc Res 85(3) Pages: 484-493
  • Peer Reviewed
• [Journal Article] RhoA and Rac1 changes in the atherosclerotic lesions of WHHLMI rabbits. (2009)
  • Author(s): H Ohkawara, T Ishibashi, M Shiomi, K Sugimoto, H Uekita, M Kamioka, Y Takuwa, T Teramoto, Y Maruyama, Y Takeishi
  • Journal Title: J Atheroscler Thromb 16(6) Pages: 846-856
  • Peer Reviewed
• [Journal Article] Gene transduction into aortic wall using plasmid-loaded cationized gelatin hydrogel-coated polyester stent-graft. (2009)
  • Author(s): H. Zhong, O. Matsui, K. Xu, T. Ogi, J. Sanada, Y. Okamoto, Y. Tabata, Y. Takuwa
  • Journal Title: J Vasc Surg 50(6) Pages: 1433-1443
  • Peer Reviewed
• [Journal Article] LOX-1-LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-d nsity lipoprotein in endothelial cells (2009)
  • Author(s): K. Sugimoto, T. Ishibashi, T. Sawamura, N. Inoue, M. Kamioka, H. Uekita, H. Ohkawara, T. Sakamoto, N. Sakamoto, Y. Okamoto, Y. Takuwa, A. Kakino, Y. Fujita, T. Tanaka, T. Teramoto, Y. Maruyama, Y. Takeishi
  • Journal Title: Cardiovasc Res 84(1) Pages: 127-136
  • Peer Reviewed
• [Journal Article] Involvement of sphingosine-1-phosphate and S1P(1) in angiogenesis: Analyses using a new S1P(1) antagonist of non-sphingosine-1-phosphate analog. (2009)
  • Author(s): K. Yonesu, Y. Kawase, T. Inoue, N. Takagi, J. Tsuchida, Y. Takuwa, S. Kumakura, F. Nara
  • Journal Title: Biochem Pharmacol 15;77(6) Pages: 1011-1020
  • Peer Reviewed
• [Journal Article] Inhibitory effect of N-palmitoylphosphatidylethanolamine on macrophage phagocytosis through inhibition of Rac1 and Cdc42 (2009)
  • Author(s): A. Shiratsuchi, M. Ichiki, Y. Okamoto, N. Ueda, N. Sugimoto, Y. Takuwa, Y. Nakanishi
  • Journal Title: J. Biochem. 145(1) Pages: 43-50
  • Peer Reviewed
• [Journal Article] 生体におけるスフィンゴシン-1-リン酸シグナル系の機能 (2009)
  • Author(s): 多久和陽、岡本安雄、杜娃、戚〓、吉岡和晃、多久和典子
  • Journal Title: 実験医学 27(13) Pages: 2068-2073
  • Peer Reviewed
• [Journal Article] A case report of a renal mixed epithelial and stromal tumor in a heterozygous S1P2 receptor deficient mouse. (2008)
  • Author(s): M. Takabatake, T. Takuwa, N. Takuw, H. Yasuno, S. Matsumoto, M. Shibutani, K. Mitsumori
  • Journal Title: J Vet Med Sci 70(5) Pages: 483-485
  • Peer Reviewed
• [Journal Article] G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependenton Rho but not Rho kinase. (2008)
  • Author(s): S. Takashima, N. Sugimoto, N. Takuwa, Y. Okamoto, K. Yoshioka, M. Takamura, S. Takata, S. Kanekob, Y. Takuwa
  • Journal Title: Cardiovasc Res 79(4) Pages: 689-697
  • Peer Reviewed
• [Journal Article] Sphingosine-1-phosphatesignaling and biological activitiesin the cardiovascular system. (2008)
  • Author(s): Y. Takuwa, Y. Okamoto, K. Yoshioka, N. Takuwa
  • Journal Title: Biochim. Biophys. Acta 1781(9) Pages: 483-488
  • Peer Reviewed
• [Journal Article] The lysophospholipid mediator sphingosine-1-phosphate promotes angiogenesis in vivo in ischemic hindlimbs of mice. (2008)
  • Author(s): O. Oyama, N. Sugimoto, X. Qi, N. Takuwa, K. Mizugishi, J. Koizumi, Y. Takuwa
  • Journal Title: Cardiovasc Res 78 Pages: 301-307
  • Peer Reviewed
• [Journal Article] Hypothalamic Neuropeptides and Appetite Response in Anorexia-Cachexia Animal. (2007)
  • Author(s): Y. Ueta, H. Hashimoto, E. Onuma, Y. Takuwa, E. Ogata
  • Journal Title: Endocr J 54(6) Pages: 831-838
  • Peer Reviewed
• [Journal Article] Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. (2007)
  • Author(s): M. Yano, T. Matsumura, T. Senokuchi, N. Ishii, Y. Murata, K. Taketa, H. Motoshima, T. Taguchi, K. Sonoda, D. Kukidome, Y. Takuwa, T. Kawada, M. Brownlee, T. Nishikawa, E. Araki
  • Journal Title: Circ Res 100(10) Pages: 1442-1451
  • Peer Reviewed
• [Journal Article] Synthesis and SAR studies of a novel class of S1P(1) receptor antagonists. (2007)
  • Author(s): T. Nakamura, K. Yonesu, Y. Mizuno, C. Suzuki, Y. Sakata, Y. Takuwa, F. Nara, S. Satoh
  • Journal Title: Bioorg Med Chem 15 Pages: 3548-3564
  • Peer Reviewed
• [Journal Article] Essential role for class II phosphoinositide 3-kinase alpha-isoform in Ca2+-induced, Rhoand Rho kinase-dependent regulation of myosin phosphatase and contraction in isolated vascular smooth muscle cells. (2007)
  • Author(s): K. Yoshioka, N. Sugimoto, N. Takuwa, Y. Takuwa
  • Journal Title: Mol Pharmacol 71(3) Pages: 912-920
  • Peer Reviewed
• [Journal Article] Parathyroid Hormone-Related Protein Induces Cachectic Syndromes without Directly Modulating the Expression of Hypothalamic Feeding-Regulating Peptides. (2007)
  • Author(s): H. Hashimoto, Y. Azuma, M. Kawasaki, H. Fujihara, E. Onuma, H. Yamada-Okabe, Y. Takuwa, E. Ogata, Y. Ueta
  • Journal Title: Clin Cancer Res 13 Pages: 292-298
  • Peer Reviewed
• [Journal Article] RhoA-dependent PAI-1 gene expression induced in endothelial cells by monocyte adhesion mediates geranylgeranyl transferase I and Ca2+ signaling. (2007)
  • Author(s): T. Sakamoto, T. Ishibashi, K. Sugimoto, N. Sakamoto, H. Ohkawara, M. Niinuma, K. Nagata, M. Kamioka, N. Sugimoto, A. Watanabe, M. Kurabayashi, Y. Takuwa, Y. Maruyama
  • Journal Title: Atherosclerosis 193(1) Pages: 44-54
  • Peer Reviewed
• [Journal Article] Ca2+-independent, inhibitory effects of cyclic AMP on Ca2+ regulation of phosphoinositide 3-kinase C2a, Rho and myosin phosphatase in vascular smooth muscle (2007)
  • Author(s): MA. Azam, K. Yoshioka, S. Ohkura, N. Takuwa, N. Sugimoto, K. Sato, Y. Takuwa
  • Journal Title: J. Pharm. Exp. Ther 320(2) Pages: 907-916
  • Peer Reviewed
• [Journal Article] DM. Nanus Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase. (2006)
  • Author(s): R. Zheng, A. Iwase, R. Shen, OB. Goodman Jr, N. Sugimoto, Y. Takuwa, DJ. Lerner
  • Journal Title: Oncogene 25(44) Pages: 5942-5952
  • Peer Reviewed
• [Journal Article] PKC phosphorylates MARCKS Ser159 not only directly but also through RhoA/ROCK. (2006)
  • Author(s): A. Tanabe, Y. Kamisuki, H. Hidaka, M. Suzuki, M. Negishi, Y. Takuwa
  • Journal Title: Biochem. Biophys. Res. Commun. 345 Pages: 156-161
  • Peer Reviewed
• [Journal Article] Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. (2006)
  • Author(s): I. Inoki, N. Takuwa, N. Sugimoto, K. Yoshioka, S. Takata, S. Kaneko, Y. Takuwa
  • Journal Title: Biochem. Biophys. Res. Commun. 346 Pages: 293-300
  • Peer Reviewed
• [Journal Article] Inhibition of Rac activation as a mechanism for negativeregulation of actin cytoskeletal reorganization and cell motility by cyclic AMP. (2005)
  • Author(s): S. Nagasawa, N. Takuwa, N. Sugimoto, H. Mabuchi, Y. Takuwa
  • Journal Title: Biochem J 385 Pages: 737-744
  • Peer Reviewed
• [Journal Article] Thrombin-induced rapid geranylgeranylation of RhoA as an essential process for RhoA activation in endothelial cells. (2005)
  • Author(s): H. Ohkawara, T. Ishibashi, T. Sakamoto, K. Sugimoto, K. Nagata, K. Yokoyama, N. Sakamoto, M. Kamioka, I. Matsuoka, S. Fukuhara, N. Sugimoto, Y. Takuwa, Y. Maruyama
  • Journal Title: J Biol Chem 18;280(11) Pages: 10182-10188
  • Peer Reviewed
• [Journal Article] RhoA and Rac mediate endothelial cell polarication and detachment induced by T-cadherin. (2005)
  • Author(s): M. Philippova, D. Ivanov, R. Allenspach, Y. Takuwa, P. Erne, T. Resink
  • Journal Title: FASEB J 19(6) Pages: 588-890
  • Peer Reviewed
• [Journal Article] Statins suppress oxidized low-density lipoprotein-induced macrophage proliferation by inactivation of small G protein -p38 MAPK pathway. (2005)
  • Author(s): T. Senokuchi, T. Matsumura, M. Sakai, M. Yano, T. Taguchi, K. Sonoda, D. Kukidome, K. Imoto, T. Nishikawa, S. Kim-Mitsuyama, Y. Takuwa, E. Araki
  • Journal Title: J. Biol. Chem. 280(8) Pages: 6627-6633
  • Peer Reviewed
• [Journal Article] スフィンゴシン1リン酸受容体による癌浸潤・転移の制御とその分子構造 (2005)
  • Author(s): 多久和典子, 杉本直俊, 多久和陽
  • Journal Title: 実験医学 23 Pages: 218-223
• [Presentation] スフィンゴシン-1-リン酸と血管新生の制御 (2010)
  • Author(s): 多久和陽
  • Organizer: 第43回加齢医学研究所シンポジウム
  • Place of Presentation: 加齢医学研究所大会議室(仙台)シンポジウム発表
  • Year and Date: 2010-03-24
• [Presentation] Masahide Asano and Yoh Takuwa HOST CELL S1P2 RECEPTOR NEGATIVELY REGULATES TUMOR GROWTH AND ANGIOGENESIS IN VIVO International Conference on Phospholipase A2 and Lipid Mediators (2009)
  • Author(s): Wa Du, Noriko Takuwa, Kazuaki Yoshioka, Yasuo Okamoto
  • Place of Presentation: National Center of Sciences(東京)
  • Year and Date: 20090525-20090528
• [Presentation] S1P2 IS AN ANGIOGENESIS-SUPPRESSIVE RECEPTOR International Conference on Phospholipase A2 and Lipid Mediators (2009)
  • Author(s): Yoh Takuwa
  • Place of Presentation: National Center of Sciences(東京)
  • Year and Date: 20090525-20090528
• [Presentation] Sphingosine-1-phosphate signaling in tumor biology THE U.S. -JAPAN COOPERATIVE CANCER RESEARCH PROGRAM WORKSHOP (2008)
  • Author(s): Yoh Takuwa, Wa Du, Noriko Takuwa, Kazuaki Yoshioka, Yasuo Okamoto
  • Place of Presentation: (平安会館)京都
  • Year and Date: 2008-03-20
• [Presentation] 尾形悦郎癌悪液質モデルラットにおける視床下部摂食関連遺伝子発現とPTHrPの関与 (2007)
  • Author(s): 上田陽一、橋本弘史、東由美子、小沼悦郎、岡部尚文、鈴木仁士、川崎展、藤原広明、多久和陽
  • Organizer: 第80回日本内分泌学会東京国際フォーラム
  • Place of Presentation: 東京
  • Year and Date: 2007-06-14
• [Presentation] Transgenic overexpression of sphingosine kinase 1a in mice provokes cardiac fibrosis but not increased spontaneous malignancy. (2007)
  • Author(s): Y. Takuwa
  • Organizer: 3ed International Cconference on Phospholopase A2 and Lipid Mediators Gland Hotel Vesuvio
  • Place of Presentation: イタリア
  • Year and Date: 2007-05-10
• [Presentation] Regulation of Akt activation and cell migration by Lysophosphatidic acid (LPA) (2006)
  • Author(s): Naotoshi Sugimoto, Noriko Takuwa, Yoh Takuwa
  • Organizer: 第20回国際生化学・分子生物学会議/第79回日本生化学会大会国立京都国際会館
  • Place of Presentation: 京都宝ヶ池プリンスホテル(京都)
  • Year and Date: 20060618-20060623
• [Presentation] S1P2受容体を介したB16メラノーマ細胞の制御 (2005)
  • Author(s): 多久和典子, 杉本直俊, 尾山治, 多久和陽
  • Organizer: 第82回日本生理学会大会
  • Place of Presentation: 仙台国際センター(仙台)
  • Year and Date: 20050518-20050520
• [Presentation] Y. Lysophosphatidic acid (LPA) receptor LPA1/Edg2 generates both the stimulatory and inhibitory signals for Rac and cell migration. (2005)
  • Author(s): Sugimoto. N, Takuwa. N, Takuwa
  • Organizer: International Union of Physiological Sciences 2005.
  • Place of Presentation: Pali Mountain, (アメリカ)
  • Year and Date: 20050407-20050410
• [Book] Vascular Biology Update (2007)
  • Author(s): 尾山治、多久和陽
  • Publisher: 医歯薬出版株式会社
• [Book] Signaling mechanisms for positive and negative regulation of cell motility by sphingosine-1-phosphate receptors. (Y. Hirabayashi, Y. Igarashi, A.H.Merrill(Eds.), Sphingolipid Biology) (2006)
  • Author(s): Y. Takuwa, N. Sugimoto, N. Takuwa, Y. Igarasi, Y. Hirabayashi
  • Total Pages: 415-425
  • Publisher: Springer
• [Remarks]
  • URL: http://web.kanazawa-u.ac.jp/~med04/
• [Patent(Industrial Property Rights)] 非ヒトノックアウト動物、並びにその用途およびその作製方法 (2011)
  • Inventor(s): 多久和陽、吉岡和晃
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許・特願2010-090078
  • Filing Date: 2011-04-09
• [Patent(Industrial Property Rights)] 癌細胞の転移を阻害する化合物をインビボの系でスクーリングする方法 (2009)
  • Inventor(s): 多久和陽 名川弘一
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許・特許第4117379号
  • Acquisition Date: 2009-05-02