Development of novel therapy targeting cancer stem cells by ROS regulation

• Project/Area Number: 24390448
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hokkaido University
• Principal Investigator: TOTSUKA yasunori 北海道大学, -, 名誉教授 (00109456)
• Co-Investigator(Kenkyū-buntansha): OHGA Noritaka 北海道大学, 大学院歯学研究科, 助教 (40548202) ; TEI Kanchu 北海道大学, 大学院歯学研究科, 教授 (80180066) ; OHIRO Yoichi 北海道大学, 大学院歯学研究科, 講師 (40301915) ; 進藤 正信 北海道大学, 歯学研究科(研究院), 教授 (20162802) ; 樋田 京子 北海道大学, 大学院・歯学研究科, 特任准教授 (40399952)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 血管新生阻害 / 腫瘍 / 微小環境 / 活性酸素 / 腫瘍血管内皮細胞 / 転移 / VEGF / 腫瘍血管内皮 / がん幹細胞 / 腫瘍血管 / 腫瘍微小環境

Outline of Final Research Achievements

Reactive Oxygen Species (ROS) are known as the origin of oxidative stress. ROS are produced in response to hypoxia and nutrient deprivation. It is reported that tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation because of the insufficient blood flow. ROS are accumulated in various cells in tumor microenvironment, and they promote cancer malignancy. In this study, we analyzed the effect on cancer stem cells and tumor blood endothelial cell that is reported to play a role as stem cell niche. ROS accumulation caused in alteration of gene expression profile both in cancer cells and tumor endothelial cells. One secreted protein from tumor endothelial cells was upregulated by ROS and attracted cancer cells. We analyzed the effect of ROS inhibition on cancer stem and tumor angiogenesis.

Research Products

• [Journal Article] Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel (2015)
  • Author(s): 1.Akiyama K., Maishi N., Ohga N., Hida Y., Ohba Y., Alam Mohammad Towfik, Kawamoto T., Ohmura H., Yamada K., Torii C., Shindoh M. and *Hida K.
  • Journal Title: Am J Pathol Volume: 185(2) Issue: 2 Pages: 572-580
  • DOI: 10.1016/j.ajpath.2014.10.017
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Tumor Endothelial Cells with High Aldehyde Dehydrogenase Activity and a Highly Angiogenic Phenotype (2014)
  • Author(s): 2.Ohmura-Kakutani H., Akiyama K., Maishi N., Ohga N., Hida Y., Kawamoto T., Iida J., Shindoh M., Tsuchiya K., Shinohara N., *Hida K
  • Journal Title: PLoS ONE Volume: 9(12) Issue: 12 Pages: e113910-e113910
  • DOI: 10.1371/journal.pone.0113910
  • NAID: 120005540289
  • Peer Reviewed / Open Access
• [Journal Article] Suprabasin as a novel tumor endothelial cell marker (2014)
  • Author(s): 3.Alam Mohammad Towfik，Nagao-Kitamoto H., Ohga N., Akiyama K., Maishi N., Kawamoto T., Shinohara N., Taketomi A., Shindoh M., Hida Y. and *Hida K
  • Journal Title: Cancer Sci Volume: 105(12) Issue: 12 Pages: 1533-1540
  • DOI: 10.1111/cas.12549
  • NAID: 120005539218
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Novel Targets for Antiangiogenic Therapy by Comparing the Gene Expressions of Tumor and Normal Endothelial Cells (2014)
  • Author(s): Otsubo T., et al., Hida Y., Ohga N., Sato H., Kai T., Matsuki Y., Takasu H., Akiyama K., Maishi N., Kawamoto T., Shinohara N., Nonomura K., Hida K.
  • Journal Title: Cancer Sci. Volume: (印刷中) Issue: 5 Pages: 560-567
  • DOI: 10.1111/cas.12394
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-induced reactive oxygen species cause chromosomal abnormalities in endothelial cells in the tumor microenvironment (2013)
  • Author(s): Kondoh M., Ohga N., Akiyama K., Hida Y., Maishi N., Alam Mohammad Towfik, Inoue N., Shindoh M. and Hida K
  • Journal Title: PLoS ONE Volume: 8(11) Issue: 11 Pages: e80349-e80349
  • DOI: 10.1371/journal.pone.0080349
  • NAID: 120005367415
  • Peer Reviewed
• [Journal Article] Lysyl oxidase secreted by tumour endothelial cells Promotes angiogenesis and metastasiso (2013)
  • Author(s): Osawa T., et al., Ohga N., Akiyama K., Hida Y., Kitayama K., Kawamoto T, , Yamamoto K., Maishi N., Kondoh M., Onodera Y., Fujie M., Nonomura K., Shindoh M., Hida K.
  • Journal Title: Br. J. Cancer Volume: 109(8) Issue: 8 Pages: 2237-2247
  • DOI: 10.1038/bjc.2013.535
  • Peer Reviewed
• [Journal Article] Expression of parathyroid hormone-related protein confers malignant potential to mucoepidermoid carcinoma (2013)
  • Author(s): Nagamine K, KitamuraT
  • Journal Title: Oncol Rep Volume: 29(6) Issue: 6 Pages: 2114-8
  • DOI: 10.3892/or.2013.2393
  • Peer Reviewed
• [Journal Article] The F-prostaglandin receptor is a novel marker for tumor endothelial cells in renal cell carcinoma (2013)
  • Author(s): Akiyama K., Ohga N., Maishi N., Hida Y., Kitayama K., Kawamoto T., Osawa T., Suzuki Y., Shinohara N., Nonomura K., Shindoh M., Hida K.
  • Journal Title: Pathol. Int. Volume: 63(1) Issue: 1 Pages: 37-44
  • DOI: 10.1111/pin.12031
  • Peer Reviewed
• [Journal Article] E1A expression might becontrol led by miR- 214incells with low adenovirus productivity (2012)
  • Author(s): Yanagawa-Matsuda A, KitamuraT, 他4名
  • Journal Title: VirusRes Volume: 170(1-2) Issue: 1-2 Pages: 85-90
  • DOI: 10.1016/j.virusres.2012.09.001
  • Peer Reviewed
• [Presentation] Dredging Method-A Conservative Approach for the Treatment of Keratocysic Odontogenic Tumor. (2014)
  • Author(s): Ohiro Y,Totsuka Y,Tei K
  • Organizer: 第26回台湾口腔外科学会学術大会
  • Place of Presentation: evergreen plaza Hotel Tainan(台南市、台湾）
• [Presentation] 術前化学放射線治療後にヘノッホ・シェーンライン紫斑病を合併した舌癌の１例 (2013)
  • Author(s): 佐藤和代、小野貢伸、阿部結奈、鎌田 卓、足利雄一、大廣洋一、戸塚靖則、鄭 漢忠
  • Organizer: 第５８回日本口腔外科学会総会・学術大会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] 粘表皮癌におけるPTHrPの発現 (2012)
  • Author(s): 長峯杏介、進藤正信、戸塚靖則
  • Organizer: 第66回日本口腔科学会総会
  • Place of Presentation: 広島国際会議場(広島)
  • Year and Date: 2012-05-17
• [Presentation] 局所進行下顎歯肉癌における術前DOC・CDDP併用放射線療法の有用性 (2012)
  • Author(s): 稗田敏雄、進藤正信、戸塚靖則, 他
  • Organizer: 第38回に本口腔外科学会北日本地方会
  • Place of Presentation: 札幌医科大学講堂(札幌)
• [Presentation] RANKLはインテグリンα2の発現とエンドサイトーシスを介したインテグリンの細胞内輸送を亢進する (2012)
  • Author(s): 我妻孝則、進藤正信、戸塚靖則, 他
  • Organizer: 第35回に本分子生物学会年会
  • Place of Presentation: 福岡国際会議場(福岡)
• [Presentation] 口腔扁平上皮癌における新規予後因子Vasohibin-1
  • Author(s): 鳥居ちさほ，大賀則孝，秋山廣輔，間石奈湖，北條敬之,大廣洋一，小野貢伸,戸塚靖則，鄭 漢忠，樋田泰浩，進藤正信，佐藤靖史, 樋田京子
  • Organizer: 第46回北海道病理談話会
  • Place of Presentation: 北海道大学（札幌市）
• [Presentation] 口腔扁平上皮癌における新規予後因子Vasohibin-1の発現解析
  • Author(s): 鳥居ちさほ，大賀則孝，秋山廣輔，間石奈湖，北條敬之,大廣洋一，小野貢伸,戸塚靖則，鄭 漢忠，樋田泰浩，進藤正信，佐藤靖史, 樋田京子
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）