Comprehensive analyses of the mechanism of bone destruction by oral cancer

• Project/Area Number: 25253098
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Tokyo Dental College (2015-2016); Tokyo Medical and Dental University (2013-2014)
• Principal Investigator: Yamaguchi Akira 東京歯科大学, 歯学部, 客員教授 (00142430)
• Co-Investigator(Kenkyū-buntansha): 坂本 啓 東京医科歯科大学, 医歯(薬)学総合研究科, 講師 (00302886) ; 栢森 高 東京医科歯科大学, 医歯(薬)学総合研究科, 助教 (10569841) ; 飯村 忠浩 愛媛大学, プロテオサイエンスセンター, その他 (20282775) ; 樋田 泰浩 北海道大学, 大学病院, 講師 (30399919) ; 間石 奈湖 北海道大学, 遺伝子病制御研究所, 特任助教 (00632423) ; 進藤 正信 北海道大学, 歯学研究科(研究院), 教授 (20162802)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥43,030,000 (Direct Cost: ¥33,100,000、Indirect Cost: ¥9,930,000); Fiscal Year 2015: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2014: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000); Fiscal Year 2013: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
• Keywords: 口腔癌 / 骨破壊 / RANKL / IL-6 / Notch / 骨吸収 / 間質細胞 / 破骨細胞

Outline of Final Research Achievements

We invested the mechanism underling bone destruction by oral cancer, and obtained the
following results. 1) Fibroblasts locating between cancer cells and bone surface produced IL-6 and its stimulate RANKL synthesis in the fibroblastic cells. 2) Oran cancer cells produced RANKL and it collaborator involved in bone resorption with RANKL synthesized by fibroblasts and osteoblasts. 3) Oral cancer cells produced CXCL2, and it stimulated RANKL production by fibroblastic cells. 4) We succeeded to generate a bone destruction model by transplantation of oral cancer cells into mandibular region of athymic mice.5) Fibroblasts locating between cancer cells and bone surface produced TGF-β and it involved in bone destruction by oral cancers.

Research Products

• [Journal Article] The Bone Regeneration Model and Primary Osteoblastic Cell Culture Used in the Analysis of Ccn3 Transgenic and Knockout Mice. (2017)
  • Author(s): Sakamoto K, Matsushita Y, Minamizato T, Katsuki Y, Katsube KI, Yamaguchi A
  • Journal Title: Methods Mol Biol. Volume: 1489 Pages: 309-324
  • Peer Reviewed
• [Journal Article] Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model (2017)
  • Author(s): Ono M, Oshima M, Ogawa M, Sonoyama W, Hara ES, Oida Y, Shinkawa S, Nakajima R , Mine A ,Hayano S, Fukumoto S , Kasugai8 S , Yamaguchi A, Tsuji T, Kuboki T
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 44522
  • DOI: 10.1038/srep44522
  • NAID: 120006535050
  • URL: https://tokushima-u.repo.nii.ac.jp/records/2005583
  • Peer Reviewed / Open Access
• [Journal Article] Xenograft model of the mandibular bone destruction of human oral cancers. (2016)
  • Author(s): Tohyama R, Kayamori K, Sato K, Hamagaki M, Sakamoto K, Yasuda H, Yamaguchi A
  • Journal Title: J Oral Patholog Med Volume: 45 Issue: 5 Pages: 356-364
  • DOI: 10.1111/jop.12376
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A ficile one-step strategy for the egeneration of conditional knockout mice to explore the role of Notch1 in oroesophageal tumorigenesis. (2016)
  • Author(s): Mandasari M, Sawangarun W, Ktsube K, Kayamori K, Yamaguchi A, Sakamoto K
  • Journal Title: Biochem Bioph Res Co Volume: 469 Pages: 761-767
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Parathyroid hormone facilitates osteogenesis differently in cancellous and cortical bones. (2016)
  • Author(s): Ogura K, Iimura T, Makino Y, Sugie-Oya A, Shimomura A, Takao-Kawabata R, Ishizuya T, Moriyama K, Yamaguchi A
  • Journal Title: Bone Reports Volume: 5 Pages: 7-14
  • DOI: 10.1016/j.bonr.2016.01.002
  • Peer Reviewed / Open Access
• [Journal Article] THBS1 is induced by TGFB1 in the cancer stroma and promotes invasion of oral squamous cell carcinoma. (2016)
  • Author(s): Pal SK, Nguyen CTK, Morita, K, Miki Y, Kayamori K, Yamaguchi A, Sakamoto K
  • Journal Title: J Oral Pathol Med Volume: 45 Issue: 10 Pages: 730-739
  • DOI: 10.1111/jop.12430
  • Peer Reviewed / Open Access
• [Journal Article] NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma (2016)
  • Author(s): Kayamori K, Katsube K, Sakamoto K, Ohyama Y, Hirai H, Yukimori A, Ohata Y, Akashi T, Saitoh M, Harada K, Harada H, Yamaguchi A
  • Journal Title: PLoS ONE Volume: 11 Issue: 4 Pages: 223-231
  • DOI: 10.1371/journal.pone.0154112
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] KRT17 is induced in oral cancer and facilitate tumor gowth. (2016)
  • Author(s): Khanom R, Nguyen CTK, Kayamori K, Zhao X, Morita K, Yamaguchi A, Sakamoto K
  • Journal Title: PlosOne Volume: 11 Issue: 8 Pages: e0161163-e0161163
  • DOI: 10.1371/journal.pone.0161163
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Changes in the spatialdistribution of sclerostin in the osteocytic lacuna-canalicular system in lveolar bone due to orthodontic forces, as detected on multimodal confocal fluorescence imaging analyses. (2015)
  • Author(s): Nishiyama Y, Matsumoto T, Lee JW, Saitou T, Imamura TMoriyama K, Yamaguchi A, Iimura I
  • Journal Title: Arch Oral Biol Volume: 60 Pages: 45-54
  • Peer Reviewed
• [Journal Article] Transforming growth factor-βsynthesized by stromal cells and cancer cells participates in bone resorption induced by oral squamous cell carcinoma (2015)
  • Author(s): Ryosuke Nakamura,Kou Kayamori,Erika Oue,Kei Sakamoto,Kiyoshi Harada,Akira Yamaguchi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 458 Issue: 4 Pages: 777-782
  • DOI: 10.1016/j.bbrc.2015.02.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aberrant expression and altered cellularlocalization of desmosomal and hemidesmosomal proteins are associated withaggressive clinicopathological features of oral squamous cell carcinoma. (2014)
  • Author(s): Zhao X, Yamaguchi A, Sakamoto K
  • Journal Title: Virchows Archiv Volume: 465 Issue: 1 Pages: 35-47
  • DOI: 10.1007/s00428-014-1594-6
  • Peer Reviewed / Open Access
• [Journal Article] Functional tooth restoration by next-generation bio-hybrid implant as a bio-hybrid artificail organ replacement therapy (2014)
  • Author(s): M.Oshima, K.Nakajima, T.Inoue, T.Tsuji, et al
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep06044
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rosmarinic acid exerts an anti-osteoporotic effect in the RANKL-induced mouse model of bone loss by promotion of osteoblastic differentiation and inhibition of osteoclastic differentiation. (2014)
  • Author(s): Lee JW, Asai M, Jeon SK, Iimura T, Yonezawa T, Cha BY, Woo JT, Yamaguchi A
  • Journal Title: Mol Nutr Food Res Volume: 59 Issue: 3 Pages: 386-400
  • DOI: 10.1002/mnfr.201400164
  • Peer Reviewed / Open Access
• [Journal Article] Functional heterogeneity of osteocytes in FGF23 production: The possible involvement of DMP1 as a direct negative regulation. (2014)
  • Author(s): Lee JW, Yamaguchi A, Iimura T
  • Journal Title: BoneKEy Reports Volume: in press
  • Peer Reviewed
• [Journal Article] Spatiotemporal disorder in endochondral ossification during axial skeleton development in the Mesp2-null mouse: A developmental etiology of spondylocostal dysostosis and spondylothoracic dysostosis. (2013)
  • Author(s): Makino Y, Takahashi Y, Tanabe R, Tamamura Y, Watanabe T, Haraikawa M, Hamagaki M, Hata K, Kanno J, Yoneda T, Saga Y, Goseki-Sone M, Kaneko K, Yamaguchi A, Iimura T
  • Journal Title: BONE Volume: 53 Issue: 1 Pages: 248-258
  • DOI: 10.1016/j.bone.2012.11.033
  • Peer Reviewed
• [Journal Article] The role of osteocytes in bone resorption during orthodontic tooth movement. (2013)
  • Author(s): Matsumoto T, Iimura T, Ogura K, Moriyama K, Yamaguchi A
  • Journal Title: J Dent Res Volume: 92 Issue: 4 Pages: 340-345
  • DOI: 10.1177/0022034513476037
  • Peer Reviewed / Open Access
• [Journal Article] The expression profiles of acidic epithelial keratins in Ameloblastoma. (2013)
  • Author(s): Pal KS, Sakamoto K, Aragaki T, Akashi T, Yamaguchi A
  • Journal Title: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology Volume: 115 Issue: 4 Pages: 523-531
  • DOI: 10.1016/j.oooo.2013.01.017
  • Peer Reviewed
• [Journal Article] RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer (2013)
  • Author(s): Kiyoshi Sato, Ji-Won Lee, Kei Sakamoto, Tadahiro Iimura, Kou Kayamori, Hisataka Yasuda, Masanobu Shindoh, Masako Ito, Ken Omura, Akira Yamaguchi
  • Journal Title: American Journal of Pathology Volume: 182 Issue: 5 Pages: 1890-1899
  • DOI: 10.1016/j.ajpath.2013.01.038
  • Peer Reviewed
• [Journal Article] CCN3 protein participates in bone regeneration as an inhibitory factor. (2013)
  • Author(s): Matsushita Y, Sakamoto K, Tamamura Y, Shibata Y, Minamizato T, Kihara T, Ito M, Katsube K, Hiraoka S, Koseki H, Harada K, Yamaguchi A.
  • Journal Title: The Journal of Biological Chemistry Volume: 288 Issue: 27 Pages: 19973-19985
  • DOI: 10.1074/jbc.m113.454652
  • Peer Reviewed
• [Journal Article] Integrated genotypic analysis of hedgehog-related genes identifies subgroups of keratocystic odontogenic tumor with distinct clinicopathological features. (2013)
  • Author(s): Shimada Y, Katsube K, Kabasawa Y, Morita K, Omura K, Yamaguchi A, Sakamoto K
  • Journal Title: Plos One Volume: 8 Issue: 8 Pages: e70995-e70995
  • DOI: 10.1371/journal.pone.0070995
  • Peer Reviewed
• [Journal Article] Roles of chemokine receptor CX3CR1 in maintaining murine bone homeostasis through the regulation of both osteoblasts and osteoclasts (2012)
  • Author(s): Hoshino A. Ueha S. Hanada S. Imai T. Ito M. Yamamoto K. Matsushima K. Yamaguchi A. Iimura T
  • Journal Title: J Cell Sci Volume: 15;126(Pt 4) Pages: 1032-45
  • DOI: 10.1242/jcs.113910
  • Peer Reviewed
• [Journal Article] Retention of bone strength by feeding of milk and dairy products in ovariectomized rats; involvement of changes in serum levels of 1alpha, 25(OH)2D3 and FGF23. (2012)
  • Author(s): Tanabe R, Haraikawa M, Sogabe N, Sugimoto A, Kawamura Y, Takasugi S, Nagata M, Nakane A, Yamaguchi A, Iimura T, Masae Goseki-Sone
  • Journal Title: J Nutr Biochem Volume: in press Issue: 6 Pages: 1000-7
  • DOI: 10.1016/j.jnutbio.2012.07.004
  • Peer Reviewed
• [Presentation] 脊椎動物の進化における骨格形成の変遷 (2016)
  • Author(s): 山口 朗
  • Organizer: 第5７回歯科基礎医学会学術大会
  • Place of Presentation: 新潟市
  • Invited
• [Presentation] 歯科基礎医学の多様性を基盤とした新たな歯科医学の展開―日本学術会議の立場から― (2016)
  • Author(s): 山口 朗
  • Organizer: 第5７回歯科基礎医学会学術大会
  • Place of Presentation: 新潟市
  • Invited
• [Presentation] 歯科医学の多様性を基盤とした新たな歯学研究の展開 (2016)
  • Author(s): 山口 朗
  • Organizer: 第70回NPO法人日本口腔科学会学術集会
  • Place of Presentation: 第70回NPO法人日本口腔科学会学術集会
  • Invited
• [Presentation] オステオネットワークの構築・維持・破綻：顎顔面骨疾患の病態解析の基盤構築 (2016)
  • Author(s): 山口 朗
  • Organizer: 第70回NPO法人日本口腔科学会学術集会
  • Place of Presentation: 第70回NPO法人日本口腔科学会学術集会
  • Invited
• [Presentation] 歯学研究における基礎と臨床のシグナル伝達 (2016)
  • Author(s): 山口 朗
  • Organizer: 第５８回歯科基礎医学会学術大会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] 我が国の今後の口腔科学研究の潮流、シンポジウム：学内外の動向から探る今後の口腔科学研究の潮流 (2016)
  • Author(s): 山口 朗
  • Organizer: 第302回東京歯科大学学会
  • Place of Presentation: 東京都
  • Invited
• [Presentation] オステオネットワークの構築・維持・破綻・回復：骨疾患の病態解明と新たな治療法の開発を求めて (2014)
  • Author(s): 山口 朗
  • Organizer: 第79回口腔病学会学術大会
  • Place of Presentation: 東京医科歯科大学、東京都
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] 歯科治療と骨代謝 (2014)
  • Author(s): 山口 朗
  • Organizer: 第29回日本レーザー歯科学術大会
  • Place of Presentation: タワーホール船堀、東京都
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] 脊椎動物上陸に伴う硬組織の適応と進化 (2014)
  • Author(s): 山口 朗
  • Organizer: 平成26年度日本解剖学会関東支部懇話会
  • Place of Presentation: 東京医科歯科大学、東京都
  • Year and Date: 2014-06-21
  • Invited
• [Presentation] Bone destruction by oral cancer (2014)
  • Author(s): Akira Yamaguchi
  • Organizer: The 26th Research Day, Faculty of Dentistry Chulalongkorn University
  • Place of Presentation: Chulalongkorn University、バンコク、タイ王国
  • Year and Date: 2014-05-13 – 2014-05-14
  • Invited
• [Presentation] 口腔癌の顎骨浸潤の病理 (2014)
  • Author(s): 山口 朗
  • Organizer: 第３２回日本口腔腫瘍学会総会
  • Place of Presentation: 札幌コンベンションセンター
  • Invited
• [Presentation] 骨形成と骨再生 (2014)
  • Author(s): 山口 朗
  • Organizer: 日本口腔外科学会第４１回教育研修会
  • Place of Presentation: 東京大学医学部
  • Invited
• [Presentation] 骨再生の分子基盤 (2014)
  • Author(s): 山口 朗
  • Organizer: バイオインテグレーション学会 第４回学術大会・総会
  • Place of Presentation: 東京大学医学部
  • Invited
• [Presentation] オステオネットワークの獲得・維持・破綻 (2013)
  • Author(s): 山口 朗
  • Organizer: 第５回しまなみ骨・関節フォーラム
  • Place of Presentation: 愛媛大学医学部
  • Invited
• [Presentation] 骨芽細胞分化と骨再生におけるCCN3の役割 (2013)
  • Author(s): 山口 朗
  • Organizer: 第５回日本CCNファミリー研究会
  • Place of Presentation: 岡山コンベンションセンター
  • Invited
• [Presentation] 骨細管系の比較形態学的解析 (2013)
  • Author(s): 山口 朗
  • Organizer: 第８６回日本整形外科学会学術総会
  • Place of Presentation: 広島国際会議場
  • Invited
• [Presentation] Role of CCN3 in osteoblast differentiation and bone regeneration (2013)
  • Author(s): 山口 朗
  • Organizer: 7th International CCN Workshop
  • Place of Presentation: Nice, France
  • Invited
• [Book] 最新の骨粗鬆症学―骨粗鬆症の最新知見― (2013)
  • Author(s): 山口 朗
  • Total Pages: 5
  • Publisher: 日本臨床社
• [Book] 口腔外科ハンドマニュアル2013 (2013)
  • Author(s): 山口 朗
  • Total Pages: 6
  • Publisher: クインテッセンス出版株式会社