Development of novel therapies by antioxidants for reactive oxidative species of tumor microenvironment in oral carcinoma

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592953
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hokkaido University
• Principal Investigator: MATSUZAWA Yusuke 北海道大学, 歯学研究科(研究院), 助教 (30351620)
• Co-Investigator(Kenkyū-buntansha): OGA Noritaka 北海道大学, 大学院歯学研究科, 助教 (40548202) ; HIDA Kyoko 北海道大学, 大学院歯学研究科, 特任准教授 (40399952)
• Project Period (FY): 2011 – 2013
• Keywords: 腫瘍血管内皮細胞 / 活性酸素 / 染色体異常 / 抗酸化剤

Research Abstract

It is known that inflammatory cells pruduce PGE-2, COX-2 in tumor stroma. Also we have found tumor endothelial cells also express these inflammatory cytokines. Thus, we hypothesized that reactive oxygen species (ROS), which is produced in inflammation, may contribute to choromosomal abnormality or genomic instability in tumor endothelial cells (TECs). Green tea cathecin, EGCG has anti-oxidant and has anti-cancer effects. We have reported that EGCG inhibited VEGF-induced cell proliferation and migration in TEC, not in NEC (Cancer Sci. 2009). In this study, we addressed whether ROS in TEC is removed by EGCG, and analyzed the effects of ROS in TEC. By ROS accumulation, TEC could survive more compared to NEC. When ROS was induced by pyocyanin, VEGF/VEGFR signal was acitivated in TEC and it was inhibited by EGCG. In addition, ROS induced aneuploidy in NEC and EGCG inhibited VEGF and aneuploidy. These results suggested that ROS induced TEC abnormality via VEGF autocrine loop.

Research Products

• [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) Pages: e80349
  • DOI: 10.1371/journal.pone.0080349
  • Peer Reviewed
• [Journal Article] A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence (2013)
  • Author(s): Akhter A., Hayashi Y., Sakurai Y., Ohga N., Hida K., Harashima H
  • Journal Title: Int J Pharm Volume: 456(1) Pages: 195-201
  • Peer Reviewed
• [Journal Article] Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis (2013)
  • Author(s): Osawa T., Ohga N., Akiyama K., Hida Y., Kitayama K., Kawamoto T., Yamamoto K. , Maishi N., Kondoh M., Onodera Y., Fujie M., Nonomura K., Shindoh M. and Hida K
  • Journal Title: Br J Cancer Volume: 109(8) Pages: 2237-2247
  • DOI: 10.1038/bjc.2013.535
  • Peer Reviewed
• [Journal Article] The effect of liposomal size on the targeted delivery of doxorubicin to Integrin alpha)v(beta)3-expressing tumor endothelial cells (2013)
  • Author(s): Kibria G., Hatakeyama H., Ohga N., Hida K., Harashima H
  • Journal Title: Biomaterials Volume: 34(22) Pages: 5617-5627
  • Peer Reviewed
• [Journal Article] An approach to transgene expression in liver endothelial cells using a liposome-based gene vector coated with hyaluronic acid (2013)
  • Author(s): Yamada Y., Hashida M., Hayashi Y., Tabata M., Hyodo M., Naznin Ara., Ohga N., Hida K., Harashima H
  • Journal Title: J Pharm Sci Volume: 102(9) Pages: 3119-3127
  • 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) Pages: 37-44
  • DOI: 10.1111/pin.12031
  • Peer Reviewed
• [Journal Article] 二段階口蓋形成術を施行した片側完全唇顎口蓋裂児における咬合関係の評価 (2013)
  • Author(s): 澁川統代子、三古谷忠、松沢祐介、伊藤裕美、曾我部いづみ、山本栄治、戸塚靖則、鄭漢忠
  • Journal Title: 北海道歯学会雑誌 Volume: 33号2巻 Pages: 140-152
  • Peer Reviewed
• [Journal Article] Development of a novel DNA aptamer ligand against primary cultured tumor endothelial cells (2012)
  • Author(s): Naznin Ara., Hyodo M., Ohga N., Hida K., Harashima H
  • Journal Title: PLoS ONE Volume: 7(12) Pages: e50174
  • Peer Reviewed
• [Journal Article] Prostacyclin receptor in tumor endothelial cells promotes angiogenesis in an autocrine manner (2012)
  • Author(s): Osawa T., Ohga N., Hida Y., Kitayama K., Akiyama K., Onodera Y., Fujie M., Shinohara N., Nonomura K., Shindoh M. , Hida K
  • Journal Title: Cancer Sci Volume: 103(6) Pages: 1038-1044
  • Peer Reviewed
• [Journal Article] Tumor-derived microvesicles induce proangiogenic phenotype in endothelial cells via endocytosis (2012)
  • Author(s): Kawamoto T., Ohga N., Akiyama K., Hirata N., Kitahara S, Maishi N., Osawa T., Yamamoto K., Kondoh M., Shindoh M., Hida Y., Hida K
  • Journal Title: PLoS ONE Volume: 7(3) Pages: e34045
  • Peer Reviewed
• [Journal Article] Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells (2012)
  • Author(s): Yamamoto K. , Ohga N. , Hida Y., Maishi N., Kawamoto T., Kitayama K., Akiyama K., Osawa T., Kondoh M., Matsuda K., Onodera Y., Fujie M., Kaga K., Hirano S, Shinohara N., Shindoh M., Hida K
  • Journal Title: Pathol Int Volume: 62(5) Pages: 309-317
  • Peer Reviewed
• [Journal Article] CXCR7 :A novel tumor endothelial marker in renal cell carcinoma (2012)
  • Author(s): Maishi N., Ohga N., Hida Y., Akiyama K., Kitayama K., Osawa T., Onodera Y., Shinohara N., Nonomura K., Shindoh M., Hida K
  • Journal Title: Am J Pathol Volume: 180(3) Pages: 1294-1307
  • Peer Reviewed
• [Journal Article] Heterogeneity of Tumor Endothelial Cells : Comparison between Tumor Endothelial Cells Isolated from Highly Metastatic and Low Metastatic Tumors (2012)
  • Author(s): Ohga N., Ishikawa S., Maishi N., Akiyama K., Hida Y., Kawamoto T., Sadamoto Y., Osawa T.,Yamamoto K., Kondoh M., Ohmura H., Shinohara N., Nonomura K., Shindoh M., Hida K
  • Journal Title: Am J Pathol Volume: 180(3) Pages: 1283-1293
  • Peer Reviewed
• [Journal Article] Tumor endothelial cells acquire drug resistance by MDR1 upregulation via VEGF signaling in tumor microenvironment (2011)
  • Author(s): Akiyama K., Ohga N., Hida Y., Kawamoto T., Sadamoto Y., Ishikawa S., Maishi N., Akino T., Kondoh M., Matsuda A., Inoue N., Shindoh M. and Hida K
  • Journal Title: J Controlled Release Volume: 153(2) Pages: 141-148
  • Peer Reviewed
• [Journal Article] Dual-ligand modification of PEGylated liposomes shows better cell selectivity and efficient gene delivery (2011)
  • Author(s): Kibria G., Hatakeyama H., Ohga N., Hida K., Harashima H
  • Journal Title: Int J Cancer Volume: 130(1) Pages: 59-70
  • Peer Reviewed
• [Journal Article] Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells (2011)
  • Author(s): Muraki C., Ohga N., Hida Y., Nishihara H., Kato Y., Tsuchiya K., Matsuda K., Totsuka Y., Shindoh M. and Hida K
  • Journal Title: Br J Cancer Volume: 130(1) Pages: 59-70
  • Peer Reviewed
• [Journal Article] HuR keeps an angiogenic switch on by stabilizing mRNA of VEGF and COX-2 in tumor endothelium (2011)
  • Author(s): Kurosu T., Ohga N., Hida Y., Maishi N., Akiyama K., Kakuguchi W., Kuroshima T., Kondo M., Akino T., Totsuka Y., Shindoh M., Higashino F. and Hida K
  • Volume: 104(5)
  • Pages: 819-829
  • Peer Reviewed
• [Journal Article] Phenotype of tumor lymphatic vessels is a prognostic factor in human tongue squamous cell carcinoma (2011)
  • Author(s): Nitta Y., Hida K., Kitamura T., Higashino F., Ohga N., Fukushima K., Shindoh M
  • Journal Title: Oncol Lett Volume: 2(1) Pages: 79-83
  • Peer Reviewed
• [Journal Article] 北海道大学病院高次口腔医療センターにおける口唇裂・口蓋裂患者の臨床統計的調査 (2011)
  • Author(s): 三古谷忠、松沢祐介、曾我部いづみ、伊藤裕美、山本栄治、澁川統代子、金子知生、三上愛、今井智子、道念正樹、村上有二、渡辺政明、中村英司、井上農夫男、戸塚靖則
  • Journal Title: 日本口蓋裂学会雑誌 Volume: 36(3) Pages: 166-173
  • Peer Reviewed
• [Journal Article] Identification of Novel Targets for Antiangiogenic Therapy by Comparing the Gene Expressions of Tumor and Normal Endothelial Cells
  • Author(s): Otsubo T.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: (in press)
  • Peer Reviewed
• [Presentation] Monocortical mandiblar bone grafting for reconstruction of alveolar cleft followed by implant placement (2013)
  • Author(s): Yusuke Matsuzawa, Tadashi Mikoya, Toyoko Shibukawa, Izumi Sogabe, Yumi Ito, Kanchu Tei
  • Organizer: report of a case.12^<th> International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies
  • Place of Presentation: Hilton Orlando Lake Buena Vista, Orland, USA
  • Year and Date: 20130505-10
• [Presentation] 歯の移植の実際と成功のポイント (2013)
  • Author(s): 松沢祐介
  • Organizer: 第58回日本口腔外科学会
  • Place of Presentation: 福岡国際会議議場・マリンメッセ福岡福岡
  • Year and Date: 2013-10-13
• [Presentation] 口腔扁平上皮癌における新規予後因子Vasohibin-1 (2013)
  • 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
  • Year and Date: 2013-10-12
• [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 (2013)
  • 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
  • Place of Presentation: パシフィコ横浜横浜
  • Year and Date: 2013-10-04
• [Presentation] Characterization of stem-like tumor endothelial cells (2012)
  • Author(s): Hida K., Omura H., Akiyama K., Ohga N., Maishi N., Kawamoto T., Kondoh ., Hida Y
  • Organizer: The 20th annual Meeting of the Japanese Vascular Biology and Medicine Organization, The 10th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Tokushima Arts Foundation for Culture, Tokushima, Japan
  • Year and Date: 20121205-07
• [Presentation] Biglycan is an autocrine angiogenic factor of tumor endothelial cells (2012)
  • Author(s): Ohga N., Yamamoto K., Hida Y., Maishi N., Kawamoto T., Shindoh M., Hida K
  • Organizer: The 20th annual Meeting of the Japanese Vascular Biology and Medicine Organization, The 10th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Tokushima Arts Foundation for Culture, Tokushima, Japan
  • Year and Date: 20121205-07
• [Presentation] Tumor endothelium acquires drugresistance by MDR1/P-gp upregulationand metronomic chemotherapycombined with P-gp inhibitor enhancesantiangiogenic activity in vivo (2012)
  • Author(s): Akiyama K., Ohga N., Hida Y., Maishi ., Alam Mohammad Towfik., Kawamoto T., Omura H., Yamada K., Torii C., Sakamoto H. Matsuda A., Hida K
  • Organizer: The 20th annual Meeting of the Japanese Vascular Biology and MedicineOrganization, The 10th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Tokushima Arts Foundation for Culture, Tokushima, Japan
  • Year and Date: 20121205-07
• [Presentation] Hypoxia induces angiogenic factors andaneuploidy in micirovascular endothelialcells (2012)
  • Author(s): Kondoh M., Ohga N., Akiyama K., Maishi N., Kawamoto T., Hida Y., Shindoh M., Hida K
  • Organizer: The 20th annual Meeting of the Japanese Vascular Biology and Medicine Organization, The 10th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Tokushima Arts Foundation for Culture, Tokushima, Japan
  • Year and Date: 20121205-07
• [Presentation] 小児の歯の移植に関する臨床統計的検討 (2012)
  • Author(s): 松沢祐介,鄭漢忠
  • Organizer: 第24回日本小児口腔外科学会
  • Place of Presentation: 愛知学院大学名古屋
  • Year and Date: 2012-11-25
• [Presentation] 口蓋裂児の舌に発生したglial choristomaの1例 (2012)
  • Author(s): 松沢祐介,三古谷忠,澁川統代子,曾我部いづみ,伊藤裕美,北村哲也,進藤正信
  • Organizer: 第57回日本口腔外科学会
  • Place of Presentation: パシフィコ横浜横浜
  • Year and Date: 2012-10-19
• [Presentation] Biglycan is a specific marker and an autocrine angiogenic factor of tumor endothelial cells (2012)
  • Author(s): Yamamoto K., Ohga N., Hida Y., Maishi N., Kawamoto T., Kitayama K., Akiyama K., Osawa T., Kondoh M., Kaga K., Shinohara N., Shindoh M., Hirano S., Hida K
  • Organizer: the 17th International Vascular Biology Meeting
  • Place of Presentation: Rhein-Main Hallen, Wiesbaden, Germany
  • Year and Date: 2012-06-05
• [Presentation] 当科における顎裂部へのインプラントの適応 (2011)
  • Author(s): 松沢祐介,三古谷忠,澁川統代子,曾我部いづみ,伊藤裕美,井上農夫男,戸塚靖則
  • Organizer: 第56回日本口腔外科学会
  • Place of Presentation: 大阪国際会議場大阪
  • Year and Date: 2011-10-23
• [Book] 今日の治療指針私はこう治療しているVolume55 (2013)
  • Author(s): 松沢祐介,総編集山口徹,北原光夫,福井次矢
  • Total Pages: 1329
  • Publisher: 医学書院