Overcome the drug resistance of oral cancers with inhibition of transporters in tumor endothelial cells

• Project/Area Number: 15K20357
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Morphological basic dentistry
• Research Institution: Hokkaido University
• Principal Investigator: Akiyama Kosuke 北海道大学, 遺伝子病制御研究所, 客員研究員 (10609100)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: がん / 腫瘍血管 / 薬剤耐性

Outline of Final Research Achievements

Chemotherapy is one of the method of cancer therapy, but the therapeutic effect is not enough because of drug resistance. It has been reported that tumor endothelial cells (TECs) show abnormal phenotype. TECs are resistant to anti-cancer drug. In this study, we tried to inhibit transporters which is related to drug resistance. Treatment of paclitaxel with transporter inhibitor inhibited TEC proliferation in vitro. In addition, treatment of paclitaxel with transporter inhibitor inhibited tumor growth compared to single paclitaxel treatment.

Research Products

• [Journal Article] Tumor endothelial cells express high pentraxin 3 levels (2016)
  • Author(s): Hida K., Maishi N., Kawamoto T., Akiyama K., Ohga N., Hida Y., Yamada K., Hojo T., Kikuchi H., Sato M., Torii C., Shinohara N., Shindoh M
  • Journal Title: Pathol Int Volume: 66 Issue: 12 Pages: 687-694
  • DOI: 10.1111/pin.12474
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of characteristics of mouse immortalized normal endothelial cells, MS1 and primary cultured endothelial cells. (2016)
  • Author(s): Hida K., Maishi N., Torii C., Yanagiya M., Annan Akuba-Muhyia Dorcas., Morimoto M., Alam Mohammad Towfik
  • Journal Title: Hokkaido J. Dent. Sci. Volume: 37 Pages: 40-48
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. (2016)
  • Author(s): N. Maishi, Y. Ohba, K. Akiyama, N. Ohga, J.I. Hamada, H. Nagao-Kitamoto, M. Alam, K. Yamamoto, T. Kawamoto, N. Inoue, A. Taketomi, M. Shindoh, Y. Hida and K. Hida.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 28039-28039
  • DOI: 10.1038/srep28039
  • NAID: 120005819304
  • Peer Reviewed / Open Access
• [Journal Article] CXCL 12-CXCR7 axis is important for tumor endothelial cell angiogenic property (2015)
  • Author(s): Yamada K., Maishi N., Akiyama K., Alam Mohammad Towfik, Ohga N., Kawamoto T., Shindoh M. Takahashi N., Kamiyama T., Hida Y., Taketomi A. and Hida K.
  • Journal Title: Int J Cancer Volume: 137(12) Issue: 12 Pages: 2825-2836
  • DOI: 10.1002/ijc.29655
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Presentation] P-glycoprotein expression dynamics in tumor blood vessels of urothelial carcinoma during chemotherapy (2016)
  • Author(s): 菊地 央，間石奈湖，秋山廣輔，森本真弘，柳谷美沙，土屋邦彦，安部崇重，樋田泰浩，原林 透，飴田 要，柏木 明，田中伸哉，松野吉宏，篠原信雄，樋田京子
  • Organizer: 第24回日本血管生物医学会学術集会
  • Place of Presentation: 長崎ブリックホール（長崎市）
  • Year and Date: 2016-12-10
• [Presentation] Tumor endothelial cells acquire drug resistance by exosomal-miR derived from high metastatic tumor (2016)
  • Author(s): Hida K., Torii C., Maishi N., Morimoto M., Akiyama K., Kawamoto T., Minami T., Yoshioka Y., Mohammad Towfik Alam, Shindoh M., Hida Y., Ochiya T
  • Organizer: The 19th International Vascular Biology Meeting
  • Place of Presentation: Sheraton Boston Hotel (USA)
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] Tumor endothelial cells in high metastatic tumors promote metastasis via biglycan (2016)
  • Author(s): Maishi N., Ohba Y., Akiyama K., Ohga N., Hamada J., Nagao-Kitamoto H., Mohammad Towfik Alam, Shindoh M., Hida Y. Hida K.
  • Organizer: The 19th International Vascular Biology Meeting
  • Place of Presentation: Sheraton Boston Hotel (USA)
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] P-glycoprotein expression dynamics in tumor blood vessels of urothelial carcinoma during chemotherapy (2016)
  • Author(s): Kikuchi H., Maishi N., Akiyama K., Morimoto M., Yanagiya M., Miyajima N., Tuchiya K., Maruyama S., Abe T., Hida Y., Harabayashi T., Ameda K., Matsumoto R., Kashiwagi A., Demura T., Tsuda M., Tanaka S., Matsuno Y., Shinohara N., Hida K.
  • Organizer: The 19th International Vascular Biology Meeting
  • Place of Presentation: Sheraton Boston Hotel (USA)
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] 抗癌剤治療前後の尿路上皮癌における腫瘍血管内皮のP-glycoprotein発現変化 (2016)
  • Author(s): 菊地 央，間石奈湖，秋山廣輔，森本真弘，柳谷美沙，宮島直人，土屋邦彦，丸山 覚，安部崇重，樋田泰浩，原林 透，飴田 要，松本隆児，柏木 明，出村孝義，津田真寿美，田中伸哉，松野吉宏，篠原信雄，樋田京子
  • Organizer: 第49回北海道病理談話会
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2016-10-15
• [Presentation] 高転移性腫瘍miRによる血管内皮におけるIL-6を介した薬剤耐性誘導 (2016)
  • Author(s): 間石奈湖，鳥居ちさほ，川本泰輔，秋山廣輔，吉岡祐亮，落谷孝広，柳谷美沙，森本真弘，菊地 央，鄭 漢忠，北川善政，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第49回北海道病理談話会
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2016-10-15
• [Presentation] 高転移性腫瘍miRによる血管内皮におけるIL-6を介した薬剤耐性誘導 (2016)
  • Author(s): 森本真弘，鳥居ちさほ，秋山廣輔，川本泰輔，間石奈湖，鄭漢忠，北川善政，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第8回日本RNA-i研究会
  • Place of Presentation: グランドプリンスホテル広島（広島市）
  • Year and Date: 2016-09-02
• [Presentation] 抗癌剤治療前後の尿路上皮癌における腫瘍血管内皮のP-glycoprotein発現変化 (2016)
  • Author(s): 菊地 央，間石奈湖，秋山廣輔，樋田京子
  • Organizer: 第25回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター（米子市）
  • Year and Date: 2016-07-21
• [Presentation] 腫瘍血管内皮細胞によるbiglycanの分泌を介したがんの転移促進 (2016)
  • Author(s): 間石奈湖，秋山廣輔，大賀則孝，浜田淳一，樋田京子
  • Organizer: 第25回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター（米子市）
  • Year and Date: 2016-07-21
• [Presentation] Tumor endothelial cells promote metastasis via biglycan secretion (2016)
  • Author(s): Maishi N., Ohba Y., Akiyama K., Ohga N., Hamada J., Mohammad Towfik Alam, Shindoh M., Hida Y., Hida K
  • Organizer: Tenth AACR-JCA Joint Conference “Breakthroughs in Cancer Research: From Biology to Therapeutics”
  • Place of Presentation: Maui (USA)
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] ROS によるbiglycan 発現誘導を介した腫瘍血管内皮細胞の血管新生能亢進 (2015)
  • Author(s): 北條敬之，間石奈湖，Mohammad T Alam，秋山廣輔，大賀則孝，進藤正信，樋田泰浩，藤澤俊明，樋田京子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-10
• [Presentation] 高転移性腫瘍miRNA はIL-6 ならびにALDH の発現亢進を介して血管内皮に薬剤耐性を誘導する (2015)
  • Author(s): 鳥居ちさほ，間石奈湖，Mohammad T Alam，秋山廣輔，大賀則孝，進藤正信，樋田泰浩，藤澤俊明，樋田京子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-10
• [Presentation] 腫瘍血管内皮細胞はbiglycan の分泌を介してがんの転移を促進する (2015)
  • Author(s): 間石奈湖，大場雄介，秋山廣輔，大賀則孝，浜田淳一，北本(永尾）宗子，Mohammad Alam T.，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Tumor endothelial cells promote metastasis via biglycan secretion (2015)
  • Author(s): Maishi N., Ohba Y., Akiyama K., Ohga N., Hamada J., Mohammad Towfik Alam, Shindoh M., Hida Y., Hida K
  • Organizer: The European Cancer Congress 2015
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-09-27
  • Int'l Joint Research
• [Presentation] 高転移性腫瘍miRによらう血管内皮におけるIL-6を介した薬剤耐性誘導 (2015)
  • Author(s): 鳥居ちさほ，秋山廣輔，川本泰輔，間石奈湖，Alam Mohammad Towfik，鄭 漢忠，戸塚靖則，進藤正信，樋田泰浩，南 敬，小坂展慶，落谷孝広，樋田京子
  • Organizer: 第112回北海道癌談話会例会
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」（北海道・札幌市）
  • Year and Date: 2015-09-12
• [Presentation] 腫瘍血管内皮細胞はbiglycanの分泌を介してがんの転移を促進する (2015)
  • Author(s): 間石奈湖，大場雄介，秋山廣輔，大賀則孝，浜田淳一，北本宗子，Alam Mohammad Towfik，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館（北海道・札幌市）
  • Year and Date: 2015-07-31
• [Presentation] 高転移性腫瘍miRNAはIL-6ならびにALDHの発現亢進を介して血管内皮に薬剤耐性を誘導する (2015)
  • Author(s): 鳥居ちさほ，秋山廣輔，川本泰輔，間石奈湖，鄭 漢忠，戸塚靖則，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館（北海道・札幌市）
  • Year and Date: 2015-07-31
• [Presentation] Suprabasin as a novel tumor endothelial cell marker (2015)
  • Author(s): Alam Mohammad Towfik，Nagao-Kitamoto H., Ohga N., Akiyama K., Maishi N., Kawamoto T, Shinohara N., Taketomi A., Shindoh M, Hida Y, Hida K
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館（北海道・札幌市
  • Year and Date: 2015-07-31
• [Presentation] 活性酸素種によるBiglycan発現誘導を介した腫瘍血管内皮細胞の血管新生能亢進 (2015)
  • Author(s): 北條敬之，間石奈湖，秋山廣輔，大賀則孝，進藤正信，樋田泰浩，藤澤俊明，樋田京子
  • Organizer: 第26回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 北海道大学学術交流会館（北海道・札幌市
  • Year and Date: 2015-07-31
• [Presentation] 腫瘍微小環境において，腫瘍由来のmiRX により血管内皮はIL-6 をオートクラインで利用し，薬剤耐性や幹細胞性を獲得している (2015)
  • Author(s): 鳥居ちさほ，秋山廣輔，川本泰輔，間石奈湖，鄭 漢忠，進藤正信，樋田泰浩，樋田京子
  • Organizer: 第69回日本口腔科学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-05-14
• [Book] 別冊BIO Clinica 慢性炎症と疾患～慢性炎症とがん (2016)
  • Author(s): 樋田京子，大賀則孝，間石奈湖，秋山廣輔，樋田泰浩
  • Total Pages: 172
  • Publisher: 北隆館
• [Remarks] 北海道大学 遺伝子病制御研究所 フロンティア研究ユニット 血管生物学研究室ホームページ
  • URL: http://www.igm.hokudai.ac.jp/vascular-biology/