悪性黒色腫の骨の転移のメカニズムの解明

2009 Fiscal Year Annual Research Report

• Project/Area Number: 20013014
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 野田 政樹 Tokyo Medical and Dental University, 難治疾患研究所, 教授 (50231725)
• Co-Investigator(Kenkyū-buntansha): 江面 陽一 東京医科歯科大学, 難治疾患研究所, 准教授 (50333456) ; 早田 匡芳 東京医科歯科大学, 難治疾患研究所, 助教 (40420252)
• Keywords: B16 / 細胞接着 / 癌細胞 / 転移 / 破骨細胞 / 悪性黒色腫

Research Abstract

癌の進展においては細胞の接着、及びインテグリンからのシグナルによる細胞の生存、増殖さらには活性化した細胞からのサイトカインの発現により骨の場合には局所のマクロファージや前駆細胞の活性化からはじまる破骨細胞の分化とその活動性の亢進がおこる。このような一連の骨に転移させる活性の高い細胞における転移のメカニズムの解明を目的とし、悪性黒色腫のマウスB16細胞についての検討を行なった。マウスB16細胞の細胞接着とその形態を観察する目的で、まず、細胞における接着反分子の解析について検討した。その結果、細胞接着反のAdhesion Complexの分子群を構成するCIZの発現がB16細胞において確認された。この発現は細胞質にあるとともにまた細胞接着反においても認められた。この分子の接着とのかかわりが推察された。悪性黒色腫の中でも特に転移活性の高いB16F10の細胞とその親株であるB16における細胞の転移活性と接着との相関を検討するとCIZのレベルがB16F10細胞において親株のB16との大きな相違が認められ、この相関が細胞転移活性に関与することが示唆された。更に、癌細胞の骨への転移によって生じる、骨の破壊に関わる破骨細胞の制御について検討を行った。この結果、破骨細胞においてはDicerの特異的なカテプシンKcreに基づくノックアウトより骨量が増加すること、海綿骨の厚さの増加がみられることが明らかになった。この転移のおける破骨破壊をもたらず破骨細胞の分化のレベルの低下は細胞において内因性であり、コンディショナルノックアウトマウスの骨髄細胞の破骨細胞への分化も抑制が観察された。以上の研究成果は悪性黒色腫の骨への転移とその骨における腫瘍に基づく骨破壊の主たる細胞である破骨細胞のメカニズムを明らかにしたものであり、今後これらの分子を抑止する薬剤の探索など癌の転移に対する対策の基盤となる起点が確立された。

Research Products

• [Journal Article] Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption (2010)
  • Author(s): Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, Kato S, Miyasaka N, Ezura Y, Noda M
  • Journal Title: Journal of Cellular Biochemistry 109 Pages: 866-75
  • Peer Reviewed
• [Journal Article] Cbl-b Enhances Runx2 Protein Stability and Augments Osteocalcin Promoter Activity in Osteoblastic Cell Lines (2010)
  • Author(s): Ampornaramveth Salingcarnboriboon, R., Pavasant, P., Noda, M.
  • Journal Title: Journal of Cellular Physiology (in press)
  • Peer Reviewed
• [Journal Article] Nemo-like kinase(NLK)expression in osteoblastic cells and suppression of osteoblastic differentiation (2010)
  • Author(s): Nifuji A, Ideno H, Ohyama Y, Takanabe R, Araki R, Abe M, Noda M, Shibuya H.
  • Journal Title: Experimental Cell Research 316 Pages: 1127-1136
  • Peer Reviewed
• [Journal Article] ANA deficiency enhances BMP-induced ectopic bone formation via transcriptional events (2009)
  • Author(s): Miyai K, Yoneda M, Hasegawa U, Toida S, Izu Y, Hemmi H, Hayata T, Ezura Y, Mizutani S, Miyazono K, Akiyoshi K, Yamamoto T, Noda M
  • Journal Title: Journal of Biological Chemistry 284 Pages: 10593-600
  • Peer Reviewed
• [Journal Article] Combinatory effects of androgen receptor deficiency and hindlimb unloading on bone (2009)
  • Author(s): Saita Y, Takashi Nakamura, Fumitaka Mizoguchi, Kazuhisa Nakashima, Tadayoshi Hayata, Yoichi Ezura, Hisashi Kurosawa, Shigeaki Kato, Masaki Noda
  • Journal Title: Thime ejournals 41 Pages: 822-8
  • Peer Reviewed
• [Journal Article] Osteoblastic Bone Formation Is Induced by Using Nanogel-Crosslinking Hydrogel as Novel Scaffold for Bone Growth Factor (2009)
  • Author(s): Hayashi C, Hasegawa U, Saita Y, Hemmi H, Hayata T, Nakashima K, Ezura Y, Amagasa T, Akiyoshi K, Noda M
  • Journal Title: Journal of Cellular Physiology 220 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Methylation status of CpG-islands in the promoter regions of signature genes during chondrogenesis of human synovium-derived mesenchymal stem cells (2009)
  • Author(s): Ezura Y, Koga H, Muneta T, Sekiya I, Noda M
  • Journal Title: Arthritis & Rheumatism 60 Pages: 1416-1426
  • Peer Reviewed
• [Journal Article] Angiotensin II type 2 receptor blockade increases bone mass (2009)
  • Author(s): Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, Inagami T, Ezura Y, Noda M
  • Journal Title: Journal of Biological Chemistry 284 Pages: 4857-64
  • Peer Reviewed
• [Presentation] The hypermethylated high-density CpG-region(-1112/-888)of the stromal cell-derived factor 1(SDF1)is demethylated in the synovium derived mesenchymal stem cells during chondrogenesis (2009)
  • Author(s): Ezura Y, Sekiya I, Muneta T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Dullard, a novel phosphatase, that dephosphorylates and degrades BMP receptors, suppresses signaling in osteoblasts (2009)
  • Author(s): Hayata T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] The identification and characterization of a new Trem-like molecule (2009)
  • Author(s): Hemmi H, Idoyaga J, Suda K, Noda M, Steinman R.M.
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Anabolic Action of PTH/PTHrP Receptor Signaling in Bone i Suppressed by a Nucleocytoplasmic Shuttling Protein CIZ (2009)
  • Author(s): Nakamoto T, Ono N, Hanyu R, Sakuma T, Hayata T, Ezura Y, Schipani E, Kronenberg HM, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Pacemaker channel HCN1 affects osteoclast function in vitro and bone remodeling in vivo (2009)
  • Author(s): Notomi T, Tanaka S, Amano H, Nakamura T, Noda M, Skerry TM, Kuno M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Sympathetic nervous tone modulates constitutively active parathyroid hormone receptor signaling in vivo (2009)
  • Author(s): Hanyu R, Takeda S, Notomi T, Hemmi H, Hayata T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Schnurri-2(SHN-2)deficiency counteracts against bone loss induced by ovariectomy (2009)
  • Author(s): Nagao M, Saita Y, Hanyu R, Hemmi H, Notomi T, Nakamoto T, Hayata T, Ezura Y, Kurosawa H, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Nanogel scaffold delivery of Prostaglandin E2 Receptor(EP4)specific agonist in combination with BMP repairs microstructure of bone produced in the defect via potentiation of transcription activity of smad response element (2009)
  • Author(s): Kamolratanakul P, Kawamata A, Yamamoto Y, Hayata T, Ezura Y, Akiyoshi K, Amagasa T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Deficiency of Ciz, Cas Interactive Zinc Finger Protein, suppresses tumor invasion into bone (2009)
  • Author(s): Sakuma T, Nakamoto T, Hayata T, Miyai K, Amagasa T, Ezura Y, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] PTH signaling and Osteopontin deficiency coordinately enhance progenitor niche for the cells to support tooth development (2009)
  • Author(s): Morishita M, Ono N, Hanyu R, Kamolratanakul P, Nagao M, Hemmi H, Hayata T, Noda M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Cbl-b enhanced Runx2 function on osteocalcin promoter activity in osteoblastic cell line (2009)
  • Author(s): Ampornaramveth, R, Pavasant, Noda, M
  • Organizer: The 31^<st> Annual Meeting of American Society for Bone and Mineral Research
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 20090911-20090915
• [Presentation] Bone biology in PTH signaling (2009)
  • Author(s): 野田政樹
  • Organizer: OGEKM Autumn Symposium 2009
  • Place of Presentation: Wien, Austria
  • Year and Date: 2009-11-21
• [Presentation] 骨形成の制御機構 (2009)
  • Author(s): 野田政樹
  • Organizer: 第20回栃木県骨・カルシウム代謝研究会
  • Place of Presentation: 栃木、日本
  • Year and Date: 2009-06-19
• [Presentation] 骨の形成とその調節機構 (2009)
  • Author(s): 野田政樹
  • Organizer: 第29回日本骨形態計測学会
  • Place of Presentation: 大阪、日本
  • Year and Date: 2009-05-29
• [Presentation] 骨と骨の分子破壊と再構築のフロンティア (2009)
  • Author(s): 野田政樹
  • Organizer: 第63回日本口腔科学会
  • Place of Presentation: 静岡、日本
  • Year and Date: 2009-04-17