Mechanisms for malignant tumor progression based on acquisition of 3-D invasiveness and regulation of epithelial morphogenesis

• Project/Area Number: 24300329
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: MATSUMOTO Kunio 金沢大学, がん進展制御研究所, 教授 (90201780)
• Co-Investigator(Renkei-kenkyūsha): SAKAI Katsuya 金沢大学, がん進展制御研究所, 助教 (10523318) ; NAKAMURA Takahiro 金沢大学, がん進展制御研究所, 助教 (70414018)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 細胞増殖因子 / 転移 / 薬剤耐性 / HGF / Met / 浸潤 / 人工アゴニスト / 環状ペプチド / がん細胞 / エピジェネティクス / PRC / MMP

Outline of Final Research Achievements

Tumor invasion, a typical characteristic of malignant tumors, is regulated not only by intrinsic gene expression profile but also extracellular factors. Met activation by HGF participates in tissue regeneration and tumor invasion. We here found that 1) aberrant proteasome-mediated proteolysis in PRC complex participates in activation of genes (e.g., MMP-2) involved in acquisition of 3-D invasiveness in human malignant mesothelioma cells, and 2) Met expression is regulated by hierarchal equilibrium between Met-low and Met-high populations in malignant melanoma cells, by which invasive and metastatic characteristics is conferred. Based on background for HGF-Met protein-protein interactions, Met-binding cyclic peptides were obtained by RaPID system, and the dimerized peptides induced Met activation and Met-mediated biological responses, in indistinguishable ability to HGF. Thus, we succeeded in generation of artificial Met-agonist / artificial HGF composed of macrocyclic peptide.

Research Products

• [Journal Article] Artificial human Met agonists based on macrocycle scaffolds (2015)
  • Author(s): Ito K, Sakai K, Suzuki Y, Ozawa N, Hatta T, Natsume T, Matsumoto K, Suga H.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 6373-6373
  • DOI: 10.1038/ncomms7373
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocyte growth factor and Met in drug discovery. (2015)
  • Author(s): Sakai K, Aoki S, Matsumoto K.
  • Journal Title: Journal of Biochemistry Volume: 印刷中
  • NAID: 120005647661
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TAS-115, a novel inhibitor of VEGFR-2 and Met, combined with erlotinib prevented re-growth of HGF-triggered erlotinib resistant lung cancer harboring EGFR mutation. (2014)
  • Author(s): Nakade J, Yano S, et al.
  • Journal Title: J Thorac Oncol Volume: 9 Issue: 6 Pages: 775-83
  • DOI: 10.1097/jto.0000000000000170
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. (2014)
  • Author(s): Tanimoto A, Yamada T, Takeuchi S, Ebi H, Kita K, Matsumoto K, Yano S.
  • Journal Title: Oncotarget Volume: 5 Pages: 4920-4928
  • NAID: 120005830567
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. (2014)
  • Author(s): Oyanagi, J., Kojima, N., Sato, H., Higashi, S., Kikuchi, K., Sakai, K., Matsumoto, K., Miyazaki, K.
  • Journal Title: Exp Cell Res. Volume: 印刷中 Issue: 2 Pages: 267-279
  • DOI: 10.1016/j.yexcr.2014.04.009
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetics and pharmacodynamics following intravenous administration of recombinant human hepatocyte growth factor in rats with renal injury. (2014)
  • Author(s): Adachi E, Hirose-Sugiura T, Kato Y, Ikebuchi F, Yamashita A, Abe T, Fukuta K, Adachi K, Matsumoto K.
  • Journal Title: Pharmacology Volume: 94 Issue: 3-4 Pages: 190-197
  • DOI: 10.1159/000363412
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HGF-Met pathway in regeneration and drug discovery. (2014)
  • Author(s): Matsumoto K, Funakoshi H, Takahashi H, Sakai K.
  • Journal Title: Biomedicines Volume: 2 Issue: 4 Pages: 275-300
  • DOI: 10.3390/biomedicines2040275
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Triple inhibition of EGFR, Met, and VEGF suppresses regrowth of HGF-triggered, erlotinib-resistant lung cancer harboring an EGFR mutation. (2014)
  • Author(s): Nakade J, MS, Takeuchi S, Nakagawa T, Ishikawa D, MD, Sano T, PhD, Nanjo S, Yamada T, Ebi H, Zhao L, MD, Yasumoto K, Matsumoto K, Yonekura K, Yano S.
  • Journal Title: J Thorcic Oncol Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Inhibitor of transforming growth factor-β potentiates fibroblast-dependent tumor cell invasion into collagen matrix by increasing secretion of hepatocyte growth factor from fibroblasts. (2014)
  • Author(s): Oyanagi J, Kojima N, Higashi S, Kikuchi K, Sakai K, Matsumoto K, Miyazaki K.
  • Journal Title: Exp Cell Res Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes (2013)
  • Author(s): Mizuho Nakayama
  • Journal Title: Cytokine Volume: XXX Issue: 3 Pages: 446-452
  • DOI: 10.1016/j.cyto.2013.04.006
  • Peer Reviewed
• [Journal Article] α-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells (2013)
  • Author(s): Michikoshi H, Nakamura T, Sakai K, (他4名)
  • Journal Title: Cancer Lett Volume: 335(2) Issue: 2 Pages: 472-478
  • DOI: 10.1016/j.canlet.2013.03.008
  • NAID: 120005254051
  • Peer Reviewed
• [Journal Article] Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans (2013)
  • Author(s): Tomoko Sugiura et al.
  • Journal Title: J. Pharm. Sci. Volume: 102(1) Issue: 1 Pages: 237-249
  • DOI: 10.1002/jps.23337
  • Peer Reviewed
• [Journal Article] HGF regulates VEGF expression via the c-Met receptor downstream pathways, PI3K/Akt, MAPK and STAT3, in CT26 murine cells (2013)
  • Author(s): Matsumura A, Kubota T, Taiyoh H, Fujiwara H, Okamoto K, Ichikawa D, Shiozaki A, Komatsu S, Nakanishi M, Kuriu Y, Murayama Y, Ikoma H, Ochiai T, Kokuba Y, Nakamura T, Matsumoto K, and Otsuji E
  • Journal Title: Int J Oncol Volume: Vol. 42: no.2 Issue: 2 Pages: 535-542
  • DOI: 10.3892/ijo.2012.1728
  • Peer Reviewed
• [Journal Article] Beneficial effect of a synthetic prostacyclin agonist, ONO-1301, in rat autoimmune myocarditis model (2013)
  • Author(s): Y. Hirata, H. Kurobe, E. Uematsu, S. Yagi, T. Soeki, H. Yamada, D. Fukuda, M. Shimabukuro, M. Nakayama, K. Matsumoto, Y. Sakai, T. Kitagawa, M. Sata
  • Journal Title: Eur. J. Pharmacol. Volume: 699 Issue: 1-3 Pages: 81-87
  • DOI: 10.1016/j.ejphar.2012.11.045
  • Peer Reviewed
• [Journal Article] The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor. (2013)
  • Author(s): Sano T, Yano S, et al.
  • Journal Title: Int J Cancer Volume: 133 Issue: 2 Pages: 505-13
  • DOI: 10.1002/ijc.28034
  • Peer Reviewed
• [Journal Article] mTOR inhibitors control erlotinib-resistance of EGFR mutant lung cancer cells triggered by HGF. (2013)
  • Author(s): Ishikawa D, Yano S, et al.
  • Journal Title: PLoS ONE Volume: 8 Issue: 5 Pages: e62104-e62104
  • DOI: 10.1371/journal.pone.0062104
  • Peer Reviewed
• [Journal Article] Interruption of the HGF paracrine loop by NK4, an HGF antagonist, reduces VEGF expression of CT26 cells. (2013)
  • Author(s): Kubota T, Matsumura A, Taiyoh H, Izumiya Y, Fujiwara H, Okamoto K, Ichikawa D, Shiozaki A, Komatsu S, Nakanishi M, Kuriu Y, Murayama Y, Ikoma H, Ochiai T, Nakamura T, Matsumoto K, Nakamura T, Otsuji E.
  • Journal Title: Oncol Report Volume: 30 Issue: 2 Pages: 567-572
  • DOI: 10.3892/or.2013.2509
  • Peer Reviewed
• [Journal Article] Oral administration of a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity for pulmonary arterial hypertension. (2013)
  • Author(s): Nakamura A, Nagaya N, Obata H, Sakai K, Sakai Y, Yoshikawa M, Hamada K, Matsumoto K, Kimura H.
  • Journal Title: Circulation J Volume: 77 Pages: 2127-2133
  • NAID: 10031178685
  • Peer Reviewed
• [Journal Article] Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis. (2013)
  • Author(s): Tsunemi S, Iwasaki T, Kitano S, Matsumoto K, Takagi-Kimura M, Kubo S, Tamaoki T, Sano H.
  • Journal Title: Arthritis Res Ther Volume: 15
  • Peer Reviewed
• [Journal Article] Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. (2013)
  • Author(s): Hayakawa H, Ichihara E, Ohashi K, Ninomiya T, Yasugi M, Takata S, Sakai K, Matsumoto K, Takigawa N, Tanimoto M, Kiura K.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 11 Pages: 1440-1446
  • DOI: 10.1111/cas.12284
  • NAID: 120005468272
  • Peer Reviewed
• [Journal Article] Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist. (2013)
  • Author(s): Xu Q, Sakai K, Nakayama M, Suzuki Y, Tambo C, Sakai Y, Matsumoto K.
  • Journal Title: Biomed Res Volume: 34 Pages: 241-250
  • NAID: 130004903851
  • Peer Reviewed
• [Journal Article] A novel long-acting prostacyclin agonist (ONO-1301) with an angiogenic effect: promoting synthesis of hepatocyte growth factor and increasing cyclic AMP concentration via IP receptor signaling. (2013)
  • Author(s): Uchida T, Hazekawa M, Yoshida M, Matsumoto K, Sakai Y.
  • Journal Title: J Pharmacol Sci Volume: 123 Pages: 392-401
  • NAID: 130003382611
  • Peer Reviewed
• [Journal Article] Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer. (2013)
  • Author(s): Zhao L, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 104 Issue: 12 Pages: 1640-6
  • DOI: 10.1111/cas.12301
  • NAID: 120005830610
  • Peer Reviewed
• [Journal Article] Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. (2013)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: PLoS ONE Volume: 8 Issue: 12 Pages: e84700-e84700
  • DOI: 10.1371/journal.pone.0084700
  • NAID: 120005368227
  • Peer Reviewed
• [Journal Article] Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes. (2013)
  • Author(s): Nakayama M.
  • Journal Title: Cytokine Volume: in press
  • Peer Reviewed
• [Journal Article] Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression. (2012)
  • Author(s): Xu Q.
  • Journal Title: Am J Physiol Volume: 302 Issue: 5 Pages: 639-648
  • DOI: 10.1007/s00776-012-0262-4
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer (2012)
  • Author(s): Yamada T, Takeuchi S, Kita K, Bando H, Nakamura T, Matsumoto K, Yano S
  • Journal Title: J Thorac Oncol Volume: 7 Issue: 2 Pages: 272-80
  • DOI: 10.1097/jto.0b013e3182398e69
  • Peer Reviewed
• [Journal Article] A synthetic prostacyclin agonist thrombozane synthase inhibitory activity, ONO-1301, protects myocardium from ischemia/reperfusion injury. (2012)
  • Author(s): Hirata Y, Shimabukuro M, Uematsu E, Soeki T, Yamada H, Sakai Y, Nakamura M, Matsumoto K, Igarashi T, Sata M
  • Journal Title: Eur J Pharmacol. Volume: 674 Issue: 2-3 Pages: 352-358
  • DOI: 10.1016/j.ejphar.2011.10.038
  • Peer Reviewed
• [Journal Article] E7050, a Met kinase inhibitor, reverses three different mechanisms of hepatocyte growth factor-induced resistance to tyrosine kinase inhibitors in EGFR mutant lung cancer cells (2012)
  • Author(s): Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, Nakamura T, Matsumoto K, Mukaida N, Nishioka Y, Sone S, Uenaka T, Yano S
  • Journal Title: Clin Cancer Res Volume: 18 Issue: 6 Pages: 1663-71
  • DOI: 10.1158/1078-0432.ccr-11-1171
  • Peer Reviewed
• [Journal Article] Arterial shear stress augments the differentiation of endothelial progenitor cells adhered to VEGF-bound surfaces. (2012)
  • Author(s): Y. Suzuki, K. Yamamoto, J. Ando, K. Matsumoto, T. Matsuda
  • Journal Title: Biochem. Biopys. Res. Commun. Volume: 423 Issue: 1 Pages: 91-97
  • DOI: 10.1016/j.bbrc.2012.05.088
  • Peer Reviewed
• [Journal Article] Hsp90 Inhibition Overcomes HGF Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis (2012)
  • Author(s): Koizumi H, Yamada T, Takeuchi S, Nakagawa T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, and Yano S
  • Journal Title: Journal of Thoracic Oncology Volume: Vol. 7: no.7 Issue: 7 Pages: 1078-1085
  • DOI: 10.1097/jto.0b013e3182519a2c
  • Peer Reviewed
• [Journal Article] Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells (2012)
  • Author(s): Yamada, T.
  • Journal Title: Clin. Cancer Res. Volume: 18 Issue: 13 Pages: 3592-3602
  • DOI: 10.1158/1078-0432.ccr-11-2972
  • Peer Reviewed
• [Journal Article] Dual inhibition of met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer (2012)
  • Author(s): Takeuchi S, Wang W, Li Q, Yamada T, Kita K, Donev IS, Nakamura T, Matsumoto K, Shimizu E, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano
  • Journal Title: Am J Pathol Volume: 181 Issue: 3 Pages: 1034-1043
  • DOI: 10.1016/j.ajpath.2012.05.023
  • Peer Reviewed
• [Journal Article] Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer (2012)
  • Author(s): Nakagawa T
  • Journal Title: Mol Cancer Ther. Volume: 11 Issue: 10 Pages: 2149-2157
  • DOI: 10.1158/1535-7163.mct-12-0195
  • Peer Reviewed
• [Journal Article] A novel prostacyclin agonist protects to airway hyperresponsiveness and remodeling in mice. (2012)
  • Author(s): Yamabayashi C.
  • Journal Title: Am J Respir Cell Mol Biol Volume: 47 Pages: 170-177
  • Peer Reviewed
• [Presentation] CBX/PRCのプロテアソーム分解を介したヒト悪性中皮腫細胞の浸潤性制御. (2014)
  • Author(s): 平井智子、酒井克也、鈴木健之、矢野聖二、高橋智聡、西内巧、松本邦夫
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 京都（京都国際会議場）
  • Year and Date: 2014-10-16
• [Presentation] Met/HGF受容体を標的とする環状ペプチドの創製. (2014)
  • Author(s): 松本邦夫、酒井克也、伊藤健一郎、菅裕明
  • Organizer: 第73回 日本癌学会総会 シンポジウム
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-27
• [Presentation] B16F10メラノーマの造腫瘍性/転移性におけるMet階層的発現の意義. (2014)
  • Author(s): 足立恵理、酒井克也、松本邦夫
  • Organizer: 第73回 日本癌学会総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-26
• [Presentation] 三次元コラーゲンゲル共培養モデルを利用したがん浸潤機構の研究: HGFとTGF-βの役割. (2014)
  • Author(s): 宮崎香、小柳潤、東昌市、菊池慶司、酒井克也、松本邦夫
  • Organizer: 第73回 日本癌学会総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-26
• [Presentation] HGF-Met pathway in metastasis, drug resistance and drug discovery (2012)
  • Author(s): Kunio Matsumoto
  • Organizer: The 17th Japan-Korea Cancer Research Workshop
  • Place of Presentation: 韓国
  • Year and Date: 2012-12-01
• [Presentation] Aberrant regulation of epigenetic silencing in 3-D tumor invasion. (2012)
  • Author(s): Katsuya Sakai
  • Organizer: The 17th Japan-Korea Cancer Research Workshop
  • Place of Presentation: 韓国
  • Year and Date: 2012-12-01
• [Presentation] Pharmacokinetic modeling of hepatocyte growth factor after repeated intravenous injections in experimental animals. (2012)
  • Author(s): Saki Takahashi
  • Organizer: 第27回日本薬物動態学会年会
  • Place of Presentation: タワーホール船堀(千葉県)
  • Year and Date: 2012-11-21
• [Presentation] リポ酸によるMet/HGF受容体活性化阻害を介したヒト肺がん細胞増殖抑制. (2012)
  • Author(s): 道越洸充
  • Organizer: 日本生物工学会2012年度大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2012-10-25
• [Presentation] マウス乳腺上皮細胞における4倍体細胞の形成と増殖能の解析. (2012)
  • Author(s): 酒井克也
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2012-09-19
• [Presentation] 肺がん細胞を用いたWnt/b-cateninシグナル抑制におけるKremenの機能解析. (2012)
  • Author(s): 中村隆弘
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2012-09-19
• [Presentation] In situ血管内皮前駆細胞捕捉・分化誘導バイオインターフェースの開発:接着細胞へのシェアストレスの影響. (2012)
  • Author(s): 鈴木芳典
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2012-06-12
• [Presentation] リポ酸によるヒト肺がん細胞増殖抑制機構の解析.
  • Author(s): 松郷誠一、道越洸充、中村隆弘、酒井克也、松本邦夫
  • Organizer: 第8回α―リポ酸研究会
  • Place of Presentation: 富山国際会議場（富山県）
• [Presentation] Kremenによる肺がん細胞におけるWnt/β-cateninシグナルの調節.
  • Author(s): 中村隆弘、酒井克也、足立恵理、松本邦夫
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] がん悪性化におけるポリコーム群クロモボックスタンパク質の機能.
  • Author(s): 酒井克也、鈴木健之、矢野聖二、高橋智聡、松本邦夫
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] TGF-β阻害剤はin vitroにおいて線維芽細胞のHGF産生の亢進を介してがん細胞の浸潤を促進する.
  • Author(s): 小柳潤、東昌市、菊地慶司、酒井克也、松本邦夫、宮崎香
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] c-Metのダウンレギュレーションを伴わない新規PGI2アゴニスト反復投与の血管新生作用.
  • Author(s): 櫨川舞、松本邦夫、酒井芳紀、原口珠実、吉田都、内田享弘
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本（熊本県）
• [Book] Hepatocyte growth factor. In “Reference Module in BiomedicalSciences” (2015)
  • Author(s): Sakai K, Nakamura T, Kinoshita T, Matsumoto K.
  • Publisher: Elsevier Inc
• [Book] “HGF”「サイトカイン・増殖因子キーワード事典」 (2015)
  • Author(s): 松本邦夫
  • Publisher: 羊土社
• [Book] “MspとMsp受容体（Ron）”「サイトカイン・増殖因子キーワード事典」 (2015)
  • Author(s): 酒井克也、松本邦夫
  • Publisher: 羊土社
• [Book] “HGF-Met系を標的とするがん創薬の意義と開発”、「次世代がん戦略研究update がん基盤生物学 －革新的シーズ育成に向けて－」 (2013)
  • Author(s): 足立恵理、酒井克也、木下富誉、松本邦夫
  • Total Pages: 336
  • Publisher: 南山堂
• [Book] “Met/HGF受容体の制御”、「細胞膜受容体」（生体の科学） (2013)
  • Author(s): 酒井克也、松本邦夫
  • Total Pages: 522
  • Publisher: 医学書院
• [Remarks] 組織の再生を促す物質 人工HGFの創製に成功！
  • URL: http://www.kanazawa-u.ac.jp/rd/24835