CD44バリアント陽性胃がん幹細胞を特異的に検出するPET診断の開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25293178
• Research Institution: Keio University
• Principal Investigator: 鈴木 秀和 慶應義塾大学, 医学部, 教授 (70255454)
• Co-Investigator(Kenkyū-buntansha): 井上 浩義 慶應義塾大学, 医学部, 教授 (10213175) ; 村上 康二 慶應義塾大学, 医学部, 教授 (50200267) ; 芝田 晋介 慶應義塾大学, 医学部, 講師 (70407089)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: CD44v9 / グルタチオン / 酸化ストレス / シスチン / 胃癌幹細胞 / trastuzumab

Outline of Annual Research Achievements

グルタチオン(GSH)増強薬投与ではMKN28の5-FU感受性は有意に抑制された。また、CD44v9-MKN28では5-FU耐性を示した。5-FU投与下でCD44s-MKN28では濃度依存性にROS誘導・GSH減少が起こったがCD44v9-MKN28では抑制された。xCT阻害物質sulfasalazine投与でCD44v9-MKN28でも5-FUによるROS誘導・GSH減少を認め、CD44v9-xCT系による抗酸化能が5-FU耐性に寄与すると考えられた。NOGマウスの皮下腫瘍の検討では、CD44s-MKN28では5-FU投与で縮小したがCD44v9-MKN28では縮小しなかった。しかし、5-FU+sulfasalazineでCD44v9-MKN28は有意に縮小した。さらに上記細胞をCagA陽性ピロリ菌に曝露したHp-CD44-MKN28細胞では有意に遊走能、浸潤能が亢進し、さらにHp-CD44v9-MKN28でより強い浸潤傾向を認めた。一方で、sulfasalazine処理Hp-CD44v9-MKN28では浸潤傾向を認めなかった。これらの細胞のNOGマウス背部移植では、CD44v9-MKN28の腫瘍体積はHp群で有意に増加した。HER2陽性のNCI-N87ではtrastuzumab用量依存性に細胞生存率は低下しROS蓄積を認めたが、CD44v9発現vectorをHER2陽性胃高分化型腺癌細胞NCI-N87に形質転換したCD44v9-NCI-N87では生存率は低下せず、ROS蓄積も認めなかった。CD44v9-NCI-N87ではMnSOD発現が上昇しHER2レベルは低下した。CD44v9陽性胃癌幹細胞の薬物（S-1, trastuzumab)に対する耐性機序を示し、CD44v9発現・xCTの安定化によるシスチン増加・細胞内GSH蓄積とROS抵抗性による耐性機序の寄与度を、これら2剤で明らかにした。5-FU耐性にはxCT増強の寄与度は高いが、trastuzumabの場合は必ずしも本系だけでなく、MnSOD量もCD44v9-NCI-N87で上昇しており、それによるROS抵抗性とHER2シグナル系の抑制作用が薬剤耐性を発揮していると考えられた。本機序の詳細を明らかにしたことで、今後CD44v9陽性胃癌幹細胞のアミノ酸代謝を標的したPET/CT診断のプローブ開発に応用できる可能性が示唆された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Causes of Carryover

27年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A prospective study on symptom generation according to spicy food intake and TRPV1 genotypes in functional dyspepsia patients. (2016)
  • Author(s): Lee, S-Y., Masaoka, T., Han, H-S., Matsuzaki, J., Hong, M-J., Fukuhara, S., Choi, H-S, Suzuki, H.
  • Journal Title: Neurogastroenterol. Motil. Volume: - Pages: -
  • DOI: 10.111/nmo.12841
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Influence of regular exercise on gastric emptying in healthy men: a pilot study. (2016)
  • Author(s): Matsuzaki, J., Suzuki, H.*, Masaoka, T., Tanaka, K., Mori, H., Kanai, T.
  • Journal Title: J. Clin. Biochem. Nutri. Volume: - Pages: -
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Profile of acotiamide in the treatment of functional dyspepsia. (2016)
  • Author(s): Ueda, M., Iwasaki, E., Suzuki H.
  • Journal Title: Clin. Exp. Gastroenterol. Volume: 9 Pages: 83-88
  • DOI: 10.2147/CEG.S72172
  • Peer Reviewed / Open Access
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016)
  • Author(s): Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C.M., Suzuki, H. et al.
  • Journal Title: Autophagy Volume: 12 Pages: 1-222
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Family history is an independent risk factor for the progression of gastric atrophy among patients with Helicobacter pylori infection. (2016)
  • Author(s): Nishizawa, T., Suzuki, H., Sakitani, K., Yamashita, H., Yoshida, S., Hata, K., Kanazawa, T., Fujiwara, N., Kanai, T., Yahagi, N., Toyoshima, O.
  • Journal Title: United European Gastroenterology Journal Volume: - Pages: -
  • DOI: 10.1177/2050640616642341
  • Peer Reviewed / Open Access
• [Journal Article] Questionnaire-Based Survey on Diagnostic and Therapeutic Endoscopies and H. pylori Eradication for Elderly Patients in East Asian Countries. (2016)
  • Author(s): Matsuzaki, J., Hayashi, R., Arakawa, T., Ueno, F., Kinoshita, Y., Joh, T., Takahashi, S., Naito, Y., Fukudo, S., Chan, F.K., Hahm, K.B., Kachintorn, U., Fock, K.M., Syam, A.F., Rani, A.A., Sollano, J.D., Zhu, Q., Fujiwara, Y., Kubota, E., Kataoka, H., Tokunaga, K., Uchiyama, K., Suzuki, H.
  • Journal Title: Digestion Volume: 93 Pages: 93-102
  • DOI: 10.1159/000440741
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endoscopic slip knot clip suturing method: An ex vivo feasibility study (with video). (2016)
  • Author(s): Nishizawa, T., Uraoka, T., Sagara, S., Suzuki, H., Akimoto, T., Kanai, T., Yahagi, N.
  • Journal Title: Gastrointest. Endosc. Volume: 83 Pages: 447-450
  • DOI: 10.1016/j-gie.2015.09.007
  • Peer Reviewed / Open Access
• [Journal Article] Association of baseline plasma des-acyl ghrelin level with the response to rikkunshito in patients with functional dyspepsia. (2016)
  • Author(s): Togawa, K., Matsuzaki, J., Kobayakawa, M., Fukushima, Y., Suzaki, F., Kasugai, K., Nishizawa, T., Naito, Y., Hayakawa, T., Kamiya, T., Andoh, T., Yoshida, H., Tokura, Y., Nagata, H., Mori, M., Kato, K., Hosoda, H., Takebayashi, T., Miura, S., Uemura, N., Joh, T., Hibi, T., Suzuki, H.
  • Journal Title: J. Gastroenterol. Hepatol. Volume: 31 Pages: 334-341
  • DOI: 10.1111/jgh.13074
  • Peer Reviewed / Open Access
• [Journal Article] Emerging treatments in neurogastroenterology: Acotiamade, a novel treatment option for functional dyspepsia. (2016)
  • Author(s): Matsushita M, Masaoka T, Suzuki H.
  • Journal Title: Neurogastroenterol Motil. Volume: 28 Pages: 631-638
  • DOI: 10.1111/nmo.12756
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of carbon dioxide insufflation in balloon-assisted enteroscopy: A systematic review and meta-analysis. (2016)
  • Author(s): Nishizawa, T., Suzuki, H.*, Fujimoto, A., Ochiai, Y., Kanai, T., Yahagi, N.
  • Journal Title: United European Gastroenterology Journal Volume: 4 Pages: 11-17
  • DOI: 10.1177/2050640615588024
  • Peer Reviewed / Open Access
• [Journal Article] Effects of preoperative proton pump inhibitor administration on bleeding after gastric endoscopic submucosal dissection: A systematic review and meta-analysis (2016)
  • Author(s): Nishizawa, T., Suzuki, H.*, Akimoto, T., Maehata, T., Kanai, T., Morizane, T., Yahagi, N.
  • Journal Title: United European Gastroenterology Journal Volume: 4 Pages: 5-10
  • DOI: 10.1177/2050640615588023
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of 10-day and 14-day triple therapy as a third-line and fourth-line regimen for Helicobacter pylori eradication: a pilot study. (2015)
  • Author(s): Mori, H., Suzuki, H.*, Matsuzaki, J., Tsugawa, H., Fukuhara, S., Miyoshi, S., Hirata, K., Seino, T., Matsushita, M., Nishizawa, T., Masaoka, T., Kanai, T.
  • Journal Title: United European Gastroenterology Journal Volume: - Pages: -
  • DOI: 10.1177/2050640615618043
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy of 10-day sitafloxacin-containing third-line rescue therapies for Helicobacter pylori strains containing the gyrA mutation. (2015)
  • Author(s): Mori, H., Suzuki, H.*, Matsuzaki, J., Tsugawa, H., Fukuhara, S., Miyoshi, S., Hirata, K., Seino, T., Matsushita, M., Masaoka, T., Kanai, T.
  • Journal Title: Helicobacter Volume: - Pages: -
  • DOI: 10.1111/hel.12286
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] First-line eradication for Helicobacter pylori-positive gastritis by esomeprazole-based triple therapy is influenced by CYP2C19 genotype. (2015)
  • Author(s): Saito Y, Serizawa H, Kato Y, Nakano M, Nakamura M, Saito H, Suzuki H, Kanai T.
  • Journal Title: World J. Gastroenterol. Volume: 21 Pages: 13548-54
  • DOI: 10.3748/wjg.v21.i48.13548
  • Peer Reviewed / Open Access
• [Journal Article] BH3-only protein Bim is associated with the degree of Helicobacter pylori-induced gastritis and its localized to the mitochondria of inflammatory cells in the gastric mucosa. (2015)
  • Author(s): Akazawa, Y., Isomoto, H., Matsuda, K., Matsushima, K., Kido, Y., Urabe,S.,Yamaguchi, N., Ohnita, K., Takeshima, F., Kondo, H., Tsugawa, H., Suzuki, H., Hirayama, T., Nakao, K., Nakashima, M.
  • Journal Title: Int. J. Med. Microbiol. Volume: 305 Pages: 553-62
  • DOI: 10.1016/j.ijmm.2015.07.002
  • Peer Reviewed / Open Access
• [Journal Article] Association of visceral fat area, smoking and alcohol consumption with reflux esophagitis and Barrett’s esophagus in Japan. (2015)
  • Author(s): Matsuzaki, J., Suzuki, H.*, Kobayakawa, M., Inadomi, J.M., Takayama, M., Makino, K., Iwao, Y., Sugino, Y., Kanai, T.
  • Journal Title: PLoS One Volume: 10 Pages: e0133865
  • DOI: 10.1371/journal.pone.0133865
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New Endoscopic Suturing Method:slip knot clip suturing. (2015)
  • Author(s): Nishizawa, T., Uraoka, T., Suzuki, H., Goto, O., Ochiai, Y., Fujimoto, A., Maehata, T., Kanai, T., Yahagi, N.
  • Journal Title: Gastrointest. Endosc. Volume: 82 Pages: 570-571
  • DOI: 10.1016/j.gie.2015.04.012
  • Peer Reviewed / Open Access
• [Journal Article] Nordihydroguaiaretic acid disrupts the antioxidant ability of Helicobacter pylori through the repression of SodB activity in vitro. (2015)
  • Author(s): Tsugawa, T., Mori, H., Matsuzaki, J., Masaoka, T., Hirayama, T., Nagasawa, H., Sakakibara, Y., Suematsu, M., Suzuki, H.
  • Journal Title: Biomed. Res. Int. Volume: 2015 Pages: 734548
  • DOI: 10.1155//2015/734548
  • Peer Reviewed / Open Access
• [Journal Article] The “two-sword fencing” technique in endoscopic submucosal dissection. (2015)
  • Author(s): Nishizawa, T., Uraoka, T., Ochiai, Y., Suzuki, H., Goto, O., Fujimoto, A., Maehata, T., Kanai, T., Yahagi, N.
  • Journal Title: Clin. Endosc. Volume: 48 Pages: 85-86
  • DOI: 10.5946/ce.2015.48.1.85
  • Peer Reviewed / Open Access
• [Journal Article] Survey of clinical practice for irritable bowel syndrome in East asian countries. (2015)
  • Author(s): Fukudo, S, .Hahm, KB, Zhu, Q., Sollano, JD., Rani, AA., Syam, AF., Kachintorn, U., Suzuki, H., Kamiya, T., Joh, T., Uchiyama, K., Naito, Y., Takahashi, S., Kinoshita, Y., Ueno, F., Yamagami, H., Chan, FK., Fock, KM,, Arakawa, T.
  • Journal Title: Digestion Volume: 91 Pages: 99-109
  • DOI: 10.1159/000369078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clarithromycin versus metronidazole as first-line Helicobacter pylori eradication: A multicenter, prospective, randomized controlled study in Japan. (2015)
  • Author(s): Nishizawa, T., Maekawa, T., Watanabe, N., Harada, N., Hosoda, Y., Yoshinaga, M., Yoshio, T., Ohta, H., Inoue, S., Toyokawa, T., Yamashita, H., Saito, H., Kuwai, T., Katayama, S., Masuda, E., Miyabayashi, H., Kimura, T., Nishizawa, Y., Takahashi, M., Suzuki, H.
  • Journal Title: J. Clin. Gastroenterol. Volume: 49 Pages: 468-71
  • DOI: 10.1097/MCG.0000000000000165
  • Peer Reviewed / Open Access
• [Journal Article] Timing of oral refeeding in acute pancreatitis: A systematic review and meta-analysis. (2015)
  • Author(s): Horibe, M., Nishizawa, T., Suzuki, H., Minami, K., Yahagi, N., Iwasaki, E., Kanai, K.
  • Journal Title: United European Gastroenterology Journal Volume: - Pages: -
  • DOI: 10.1177/2050640615612368
  • Peer Reviewed / Open Access
• [Journal Article] Helicobacter pylori: Helicobacter pylori gastritis-a novel distinct disease entity. (2015)
  • Author(s): Suzuki, H.*, Mori, H.
  • Journal Title: Nature Rev. Gastroenterol. Hepatol. Volume: 12 Pages: 556-557
  • DOI: 10.1038/nrgastro.2015.158
  • Peer Reviewed / Open Access
• [Journal Article] Role of microRNAs-221/222 in digestive systems. (2015)
  • Author(s): Matsuzaki, J., Suzuki, H.
  • Journal Title: J. Clin. Med. Volume: 4 Pages: 1566-1577
  • DOI: 10.3390/jcm4081566
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Editorial: Helicobacter pylori and pathogenesis. (2015)
  • Author(s): Tomoda, A., Kamiya, S., Suzuki, H.
  • Journal Title: BioMed. Res. Int. Volume: 304768 Pages: 2
  • DOI: 10.1155/2015/304768
  • Peer Reviewed / Open Access
• [Journal Article] Letter: Prompt endoscopy in Asians with uninvestigated dyspepsia - authors' reply. (2015)
  • Author(s): Chen, S.L., Gwee, K.A., Lee, J.S., Miwa, H., Suzuki, H., Guo, P., Hao, Y.T., Chen, M.H.
  • Journal Title: Aliment. Pharm. Ther. Volume: 41 Pages: 793
  • DOI: 10.1111/apt.13131
  • Peer Reviewed / Open Access
• [Journal Article] Proton pump inhibitor alone vs proton pump inhibitor plus mucosal protective agents for endoscopic submucosal dissection-induced ulcer: a systematic review. (2015)
  • Author(s): Nishizawa, T., Suzuki, H.*, Kanai, T., Yahagi, N.
  • Journal Title: J. Clin. Biochem. Nutr. Volume: 56 Pages: 85-90
  • DOI: 10.3164/jcbn.14-101
  • Peer Reviewed / Open Access
• [Journal Article] Evidence-based clinical practice guidelines for functional dyspepsia. (2015)
  • Author(s): .Miwa, H., Kusano, M., Arisawa, T., Oshima, T., Kato, M., Joh, T., Suzuki, H., Tominaga, K., Nakada, K., Nagahara, A., Futagami, S., Manabe, N., Inui, A., Haruma, K., Higuchi, K., Yakabi, K., Hongo, M., Uemura, N., Kinoshita, Y., Sugano, K., Shimosegawa, T.
  • Journal Title: J. Gastroenterol. Volume: 50 Pages: 125-139
  • DOI: 10.1007/s00535-014-1022-3
  • Peer Reviewed / Open Access
• [Presentation] 胃発がんに関わるピロリ菌感染宿主細胞のオートファジー発現調節機構 (2016)
  • Author(s): 津川仁、森英毅、三好佐和子、柏崎有紀、松崎潤太郎、佐藤聡、井本正哉、末松誠、鈴木秀和
  • Organizer: 第88回日本胃癌学会総会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-03-19
• [Presentation] Repression of autophagy in gastric epithelial cells infected with H. pylori induces CD44 expression through the accumulation of CagA oncoprotein. (2015)
  • Author(s): Tsugawa H., Kashiwazaki Y., Mori H., Matsuzaki J., Masaoka T., Suematsu M., Suzuki H.
  • Organizer: 10th World Congress for Microcirculation
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] CD44発現に繋がるピロリ菌感染宿主細胞キャラクター (2015)
  • Author(s): 津川仁、柏崎有紀、森英毅、松崎潤太郎、佐藤聡、金井弥栄、井本正哉、末松誠、鈴木秀和
  • Organizer: 第21回日本ヘリコバクター学会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2015-06-26
• [Presentation] CagA蓄積性オートファジー不全胃癌細胞にH. pylori感染が与える影響 (2015)
  • Author(s): 森英毅、津川仁、松崎潤太郎、岩崎栄典、西澤俊宏、正岡建洋、金井隆典、鈴木秀和
  • Organizer: 第43回日本潰瘍学会
  • Place of Presentation: 沖縄科学技術大学院大学（沖縄県恩納村）
  • Year and Date: 2015-06-19
• [Presentation] Overexpression of CD44v9 in gastric cancer cells confers resistance to trastuzumab by inducing antioxidant enzymes that inhibit tumor cell death induced by oxidative stress (2015)
  • Author(s): Hideki Mori, Hidekazu Suzuki, Juntaro Matsuzaki, Hitoshi Tsugawa, Sawako Miyoshi, Tatsuhiro Masaoka, Takanori Kanai
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: ワシントンDC(米国）
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] 酸化ストレス抵抗性胃がん幹胞におけるTrastuzumab耐性メカニズムの解明 (2015)
  • Author(s): 森英毅、津川仁、鈴木秀和
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2015-04-23
• [Presentation] オートファジー不全胃癌細胞株に対してH. pylori感染が与える影響の検討 (2015)
  • Author(s): 森英毅、津川仁、鈴木秀和
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2015-04-23
• [Book] Helicobacter pylori (2016)
  • Author(s): Hidekazu Suzuki, Robin Warren, Barry Marshall eds.
  • Total Pages: 267
  • Publisher: Springer Japan