Analyses of influence by Warburg Effect small molecular Metbolites via Cancer-Stroma interactions

• Project/Area Number: 22590342
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: FUJII GEN 独立行政法人国立がん研究センター, 研究所, 主任研究員 (90321877)
• Project Period (FY): 2010-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: がん間質相互作用 / ワールブルグ効果 / 遺伝子発現 / 乳酸 / ピルビン酸 / ラミニン5 / 共培養

Research Abstract

Local fluctuations of small molecular metabolic products concentration, like lactate or pyruvate produced with Warburg effect, were frequently seen in and around cancer tissue. In this research plan, we investigate molecular influences and mechanism of unique expression due to these metabolites concentration changes, via cancer - stroma interaction, for organization, maintenance, and exacerbation of cancer.
Using co-cultured cell model system composed with cancer cell and stroma cell, we successfully perused semi-independent expression profiles of each cell group from integrated DNA chip expression data with novel bio-informatics techniques. Several gene products were extracted, and certified as these expressions were specifically responded to those metabolite concentration changes. Molecular signal transduction pathways were presumed by experiments using reagents showing resembled molecular - structure with small molecular metabolites, inhibitors, and activators for Warburg effect.

Research Products

• [Journal Article] Bi-directional regulation between adiponectin and plasminogen activator-inhibitor-1 in 3T3-L1 cells (2014)
  • Author(s): Komiya M, Fujii G, Takahashi M, Shimura M, Noma N, Shimizu S, Onuma W, Mutoh M
  • Journal Title: IN VIVO Volume: 28 Pages: 13-19
  • Peer Reviewed
• [Journal Article] Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in Apc^<Min/+>mice (2014)
  • Author(s): Shimizu S, Fujii G, Takahashi M, Nakanaishi R, Komiya M, Shimura M, Noma N, Onuma W, Yano T, Mutoh M
  • Journal Title: J Clin Biochem Nutr Volume: 54 Pages: 95-101
  • NAID: 130004879356
  • Peer Reviewed
• [Journal Article] Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in <i>Apc</i>^Min/+ mice (2014)
  • Author(s): Shimizu S, Fujii G, Takahashi M, Nakanaishi R, Komiya M, Shimura M, Noma N, Onuma W, Yano T, Mutoh M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 54 Issue: 2 Pages: 95-101
  • DOI: 10.3164/jcbn.13-91
  • NAID: 130004879356
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Bi-directional regulation between adiponectin and plasminogen activator-inhibitor-1 in 3T3-L1 cells. (2014)
  • Author(s): Komiya M, Fujii G, Takahashi M, Shimura M, Noma N, Shimizu S, Onuma W, Mutoh M.
  • Journal Title: IN VIVO Volume: 28 Pages: 13-19
  • Peer Reviewed
• [Journal Article] Involvement of Mitochondrial Reactive Oxygen Species in Gastric Carcinogenesis (2013)
  • Author(s): Masato Tamura, Michihiro Mutoh, Gen Fujii, Hirofumi Matsui
  • Journal Title: Jornal of Gastrointestinal & Digestive System Volume: 3(4) Issue: 04 Pages: 150-150
  • DOI: 10.4172/2161-069x.1000150
  • Peer Reviewed
• [Journal Article] Prevention and intervention trials for colorectal cancer (2013)
  • Author(s): Komiya M, Fujii G, Takahashi M, Iigo M, Mutoh M
  • Journal Title: Japanese J Clin Oncol Volume: 43 Pages: 685-94
  • Peer Reviewed
• [Journal Article] Suppression of intestinal polyp development through inhibition of P-glycoprotein by verapamil in Apc^<Min/+>mice (2013)
  • Author(s): Fujimoto K, Fujii G, Mutoh M, Mochida Y, Tanaka H, Wada M
  • Journal Title: Eur J Cancer Prev Volume: 22 Pages: 8-10
  • Peer Reviewed
• [Journal Article] Involvement of inflammatory factors in pancreatic carcinogenesis and preventive effects of anti-inflammatory agents (2013)
  • Author(s): Takahashi M, Mutoh M, Ishigamori R, Fujii G, Imai T
  • Journal Title: Semin in Immunopathol Volume: 35 Pages: 203-227
  • Peer Reviewed
• [Journal Article] Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours (2013)
  • Author(s): Miyanaga A, Honda K, Tsuta K, Masuda M, Yamaguchi U, Fujii G, Miyamoto A, Shinagawa S, Miura N, Tsuda H, Sakuma T, Asamura H, Gemma A, Yamada T
  • Journal Title: Ann Oncol Volume: 24 Pages: 84-90
  • Peer Reviewed
• [Journal Article] アディポネクチンと大腸がん (2013)
  • Author(s): 武藤倫弘、藤井元
  • Journal Title: 分子消化器病 Volume: 10 Pages: 52-57
• [Journal Article] Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours. (2013)
  • Author(s): Miyanaga, A., Honda, K., Tsuta, K., Masuda, M., Yamaguchi, U., Fujii, G., Miyamoto, A., Shinagawa, S., Miura, N., Tsuda, H., Sakuma, T.,, Asamura, H., Gemma, A., Yamada, T.
  • Journal Title: Ann Oncol. Volume: 24 Issue: 1 Pages: 84-90
  • DOI: 10.1093/annonc/mds215
  • Peer Reviewed
• [Journal Article] Involvement of inflammatory factors in pancreatic carcinogenesis and preventive effects of anti-inflammatory agents. (2013)
  • Author(s): Takahashi, M., Mutoh, M., Ishigamori, R., Fujii, G., Imai, T.
  • Journal Title: Semin in Immunopathol, Volume: 35 Issue: 2 Pages: 203-227
  • DOI: 10.1007/s00281-012-0340-x
  • Peer Reviewed
• [Journal Article] Prevention and Intervention Trials for Colorectal Cancer. (2013)
  • Author(s): Komiya, M., Fujii, G., Takahashi, M., Iigo, M., Mutoh, M.
  • Journal Title: Japanese J Clin Oncol. Volume: in press
  • Peer Reviewed
• [Journal Article] Novel compound SK-1009 suppresses IL-6 expression through modulation of activation of NF-kappaB pathway (2012)
  • Author(s): Shimura M, Yamamoto M, Fujii G, Takahashi M, Komiya M, Noma N, Tanuma S, Yanaka A, Mutoh M
  • Journal Title: Biol Pharm Bull Volume: 35 Pages: 2186-2191
  • Peer Reviewed
• [Journal Article] Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-A^y mice (2012)
  • Author(s): Ueno T, Teraoka N, Takasu S, Nakano K, Takahashi M, Yamamoto M, Fujii G, Komiya M, Yanaka A, Keiji Wakabayashi K, Mutoh M
  • Journal Title: Asian Pac J Cancer Prev Volume: 13 Pages: 4067-4073
  • Peer Reviewed
• [Journal Article] Searching for effective colon cancer prevention methods targeting adipocytokines (2012)
  • Author(s): Mutoh, M., Fujii, G., Yamamoto, M., Takahashi, M
  • Journal Title: Ulcer Res Volume: 39 Pages: 80-84
  • NAID: 10030578755
  • Peer Reviewed
• [Journal Article] Effects of triglyceride on colon epithelial cells during colon carcinogenesis (2012)
  • Author(s): Nakano, K., Yamamoto, M., Takahashi, M., Fujii, G., Hifumi, Y., Shimura, M., Nakanishi, R., Komiya, M., Yanaka, A., Mutoh, M
  • Journal Title: Ulcer Res Volume: 39 Pages: 196-200
  • NAID: 10031061748
  • Peer Reviewed
• [Journal Article] Synergistic suppression of mice intestinal tumorigenesis by angiotensin II receptor blocker and metformin (2012)
  • Author(s): Hifumi, Y., Fujii, G., Takahashi, M., Yamamoto, M., Nakano, K., Nakanishi, R., Shimura, M., Ishigamori, R., Yanaka, A., Mutoh, M
  • Journal Title: Ulcer Res Volume: 39 Pages: 201-206
  • NAID: 10031061770
  • Peer Reviewed
• [Journal Article] Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-Ay mice. (2012)
  • Author(s): Ueno, T., Teraoka, N., Takasu, S., Nakano, K., Takahashi, M., Yamamoto, M., Fujii, G., Komiya, M., Yanaka, A., Wakabayashi, K., Mutoh, M.
  • Journal Title: Asian Pac. J. Cancer Prev. Volume: 13 Issue: 8 Pages: 4067-4073
  • DOI: 10.7314/apjcp.2012.13.8.4067
  • Peer Reviewed
• [Journal Article] Novel Compound SK-1009 Suppresses Interleukin-6 Expression through Modulation of Activation of Nuclear Factor-KappaB Pathway (2012)
  • Author(s): Shimura, M., Yamamoto, M., Fujii, G., Takahashi, M., Komiya, M., Noma, N., Tanuma, S., Yanaka, A., Mutoh, M.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 35 Issue: 12 Pages: 2186-2191
  • DOI: 10.1248/bpb.b12-00575
  • NAID: 130001872056
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Role of adipocytokines in colorectal carcinogenesis (2011)
  • Author(s): Fujii, G., Yamamoto, M., Takahashi, M., and Mutoh, M
  • Journal Title: Curr. Res. in Cancer Volume: 5 Pages: 39-48
  • Peer Reviewed
• [Journal Article] Role of adipocytokines in colorectal carcinogenesis (2011)
  • Author(s): Fujii G, Ymamoto M, et al
  • Journal Title: Curr.Res.in Cancer Volume: 5 Pages: 39-48
• [Presentation] Role of hyperlipidemia in intestinal carcinogenesis in association with lipoprotein receptor (2013)
  • Author(s): Michihiro Mutoh, Gen Fujii, Masami Komiya, Mami Takahashi, Hitoshi Nakagama
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference
  • Place of Presentation: Maui, Hawaii, USA
• [Presentation] Global(All-over)なメチル化状態のスクリーニング的定量方法の確立 (2013)
  • Author(s): 藤井元、武藤倫弘、小宮雅美、中西るり、志村美聖、野間寛陽、清水聡美、尾沼若奈、中釜斉
  • Organizer: 第20回日本がん予防学会
  • Place of Presentation: 渋谷
• [Presentation] 大腸がん細胞増殖における低密度リポ蛋白受容体の役割 (2013)
  • Author(s): 藤井元、中西るり、小宮雅美、高橋真美、志村美聖、野間寛陽、清水聡美、尾沼若奈、武藤倫弘
  • Organizer: 第24回日本消化器癌発生学会
  • Place of Presentation: 金沢
• [Presentation] LDL受容体遺伝子のノックダウンは大腸がん培養細胞株の増殖を抑制する (2013)
  • Author(s): 藤井元、武藤倫弘、小宮雅美、高橋真美、志村美聖、野間寛陽、清水聡美、中釜斉
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Global（All-over）なメチル化状態のスクリーニング的定量方法の確立 (2013)
  • Author(s): 藤井 元、武藤倫弘、小宮雅美、中西るり、志村美聖、野間寛陽、清水聡美、尾沼若奈、中釜 斉
  • Organizer: 第20回日本がん予防学会
  • Place of Presentation: 日本薬学会長井記念館（東京都渋谷区）
• [Presentation] 大腸がん細胞増殖における低密度リポ蛋白受容体の役割 (2013)
  • Author(s): 藤井 元、中西るり、小宮雅美、高橋真美、志村美聖、野間寛陽、清水聡美、尾沼若奈、武藤倫弘
  • Organizer: 第24回日本消化器癌発生学会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
• [Presentation] LDL受容体遺伝子のノックダウンは大腸がん培養細胞株の増殖を抑制する (2013)
  • Author(s): 藤井 元、武藤倫弘、小宮雅美、高橋真美、志村美聖、野間寛陽、清水聡美、中釜斉
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Role of hyperlipidemia in intestinal carcinogenesis in association with lipoprotein receptor. (2013)
  • Author(s): Michihiro Mutoh, Genn Fujii, Masami Komiya, Mami Takahashi, Hitoshi Nakagama
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Confere
  • Place of Presentation: Maui, Hawaii, USA
• [Presentation] Combination effects of angiotensin II receptor blocker and metformin on suppression of intestinal polyp formation in Min mice (2012)
  • Author(s): Akinori YANAKA, Yoshie HIFUMI, Gen FUJII, Mami TAKAHASHI, Masafumi YAMAMOTO, Katsuya NAKANO, Misato SHIMURA, Michihiro MUTOH
  • Organizer: Digestive Disease Week
  • Place of Presentation: SanDiego, California, USA
• [Presentation] Minマウス腸ポリープ生成抑制に対するロサルタン+メトホルミンの相乗的効果 (2012)
  • Author(s): 藤井元、山本真史、高橋真美、野間寛陽、志村美聖、武藤倫弘
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] Minマウス腸ポリープ生成抑制に対するロサルタン＋メトホルミンの相乗的効果 (2012)
  • Author(s): 藤井 元、山本真史、高橋真美、野間寛陽、志村美聖、武藤倫弘
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] トウモロコシ繊維によるApcMin/+マウスにおける腸ポリープ数の減少 (2012)
  • Author(s): 藤本京子、櫻井瞳、波多江日成子、吉留弘子、木本裕、小川浩一、藤井 元、武藤倫弘、 和田守正
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Angiotensi II受容体格抗薬およびbiagnide薬の併用によるMinマウス腸ポリープ生成抑制 (2012)
  • Author(s): 一二三佳恵・高橋真美・藤井元, 他
  • Organizer: 個体レベルでのがん研究支援活動ワークショップ<個体レベルのがん研究のパラダイム>
  • Place of Presentation: 大津市
• [Presentation] 低密度リポタンパク受容体欠損のマウス大腸異常腺窩巣生成に対する影響 (2012)
  • Author(s): 中野勝也・藤井元, 他
  • Organizer: 個体レベルでのがん研究支援活動ワークショップ<個体レベルのがん研究のパラダイム>
  • Place of Presentation: 大津市
• [Presentation] 大腸aberant crypt foci生成に対するlow-density lipoprotein受容体欠損の影響 (2012)
  • Author(s): 中野勝也・武藤倫弘・高橋真美・藤井元, 他
  • Organizer: 第8回日本消化管学会学術総会
  • Place of Presentation: 仙台市
• [Presentation] メトホルミン及びロサルタンの併用投与によるMinマウス腸ポリープ生成抑制効果の検討 (2011)
  • Author(s): 一二三佳恵・藤井元, 他
  • Organizer: 第39回日本潰瘍学会
  • Place of Presentation: つくば市
• [Presentation] 大腸aberant crypt fociにおけるlow-density lipoprotein受容体の寄与 (2011)
  • Author(s): 中野勝也・高橋真美・藤井元, 他
  • Organizer: 第39回日本潰瘍学会
  • Place of Presentation: つくば市
• [Book] アディポネクチンと大腸がん (2013)
  • Author(s): 武藤倫弘,藤井元
  • Publisher: 分子消化器病
• [Book] 大腸がんとアディポサイトカイン、脂質異常 (2012)
  • Author(s): 武藤倫弘、藤井元、高橋真美
  • Publisher: The Lipid
• [Book] 分子スポーツ医学を利用したがん予防の可能性 (2012)
  • Author(s): 武藤倫弘,藤井元
  • Publisher: 週刊医学のあゆみ