Targeting urothelial cancer by inhibiting drug transporter of tumor blood vessels

• Project/Area Number: 17K11116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Hokkaido University
• Principal Investigator: Shinohara Nobuo 北海道大学, 医学研究院, 教授 (90250422)
• Co-Investigator(Kenkyū-buntansha): 菊地 奈湖 (間石奈湖) 北海道大学, 歯学研究院, 助教 (00632423) ; 樋田 泰浩 北海道大学, 大学病院, 准教授 (30399919) ; 大澤 崇宏 北海道大学, 大学病院, 助教 (60374443)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 薬剤耐性 / 腫瘍血管内皮 / 尿路上皮がん / P-glycoprotein / IL-8 / 薬物耐性 / 腫瘍血管 / 尿路上皮癌 / トランスポーター / 血管新生

Outline of Final Research Achievements

P-glycoprotein (P-gp), ATP binding cassette transporter, causes drug resistance. We have reported that tumor endothelial cells (TECs) are resistant to paclitaxel (PTX) with P-gp upregulation. PTX is often selected in salvage chemotherapy for urothelial carcinoma (UC), however its outcomes are limited. We hypothesized that TEC P-gp is the cause of this situation. We demonstrated that the number of P-gp positive TECs increased after chemotherapy in UC. High P-gp expression in TECs was correlated with poor prognosis in patients with UC.
As the mechanism, chemotherapy elevated P-gp expression in ECs via increasing tumor IL-8 secretion. When the P-gp inhibitor was combined with PTX, tumor growth and metastasis were more reduced with anti-angiogenic effect compared to PTX alone. It was suggested that chemotherapy causes inflammatory changes in tumors, which induce P-gp expression in TECs and cause drug resistance. Targeting P-gp in TECs can be a novel strategy to overcome drug resistance.

Academic Significance and Societal Importance of the Research Achievements

抗癌剤により腫瘍細胞の性質変化がおこることはよく知られているが、腫瘍間質細胞の一つである腫瘍血管内皮細胞も性質変化を起こしていることは新たな発見である。その性質変化の一つである腫瘍血管内皮細胞の薬剤トランスポーター発現上昇が尿路上皮癌の予後不良因子であることがわかり、薬剤耐性克服の治療戦略として腫瘍血管内皮細胞の薬剤トランスポーターを標的とする必要があることが証明された。
さらに薬剤トランスポーターの発現が上昇するメカニズムとして腫瘍細胞由来のIL-8が関与していることがわかった。本研究は薬剤耐性克服のために標的とすべき分子が同定され、新たな治療法開発につながる研究である。

Research Products

• [Journal Article] Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment (2019)
  • Author(s): Dorcas Akuba Muhyia Annan, Nako Maishi, Tomoyoshi Soga, Randa Dawood, Cong Li, Hiroshi Kikuchi, Takayuki Hojo, Masahiro Morimoto, Tetsuya Kitamura, Mohammad Towfik Alam, Kazuyuki Minowa, Nobuo Shinohara, Jin-Min Nam, Yasuhiro Hida, Kyoko Hida
  • Journal Title: Cell Communication and Signaling Volume: 17 Issue: 1 Pages: 169-169
  • DOI: 10.1186/s12964-019-0478-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of immortalized human tumor endothelial cells from renal cancer (2019)
  • Author(s): Nako Maishi, Hiroshi Kikuchi, Masumi Sato, Hiroko Nagao-Kitamoto, Dorcas A. Annan, Shogo Baba, Takayuki Hojo, Misa Yanagiya, Yusuke Ohba, Genichiro Ishii, Kenkichi Masutomi, Nobuo Shinohara, Yasuhiro Hida, Kyoko Hida
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 18 Pages: 4595-4595
  • DOI: 10.3390/ijms20184595
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of Tumor Endothelial Cells in Cancer Progression (2018)
  • Author(s): Hida K., Maishi N., Dorcas A. Annan, Hida Y.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 5 Pages: 1272-1272
  • DOI: 10.3390/ijms19051272
  • Peer Reviewed / Open Access
• [Journal Article] Abnormalities of tumor endothelial cells and cancer progression (2018)
  • Author(s): Hida K., Maishi N.:
  • Journal Title: Oral Sci Int Volume: 15(1) Issue: 1 Pages: 1-6
  • DOI: 10.1016/s1348-8643(17)30041-1
  • NAID: 10031168583
  • Peer Reviewed / Open Access
• [Journal Article] The usefulness of testosterone administration in identifying false-positive elevation of serum human chorionic gonadotropin in patients with germ cell tumor. (2018)
  • Author(s): 11.Takizawa A, Kawai K, Kawahara T, Kojima T, Maruyama S, Shinohara N, Akamatsu S, Kamba T, Nakamura T, Ukimura O et al
  • Journal Title: Journal of cancer research and clinical oncology Volume: 144 Issue: 1 Pages: 109-115
  • DOI: 10.1007/s00432-017-2520-5
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials. (2017)
  • Author(s): 3.Noguchi S, Shinohara N, Ito T, Ohtsu A, Ravaud A, Jerusalem G, Ohno N, Gallo J, Bouillaud E, Fan J et al
  • Journal Title: Oncology Volume: 92 Issue: 5 Pages: 243-254
  • DOI: 10.1159/000457904
  • Peer Reviewed / Open Access
• [Journal Article] Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study. (2017)
  • Author(s): 5.Oya M, Tomita Y, Fukasawa S, Shinohara N, Habuchi T, Rini BI, Fujii Y, Kamei Y, Umeyama Y, Bair AH et al
  • Journal Title: Cancer science Volume: 108 Issue: 6 Pages: 1231-1239
  • DOI: 10.1111/cas.13232
  • Peer Reviewed / Open Access
• [Journal Article] Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study (2017)
  • Author(s): 6.Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Kimura G, Yonese J, Yao M et al
  • Journal Title: apanese journal of clinical oncology Volume: 47 Issue: 7 Pages: 639-646
  • DOI: 10.1093/jjco/hyx049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perioperative morbidity and mortality of octogenarians treated by radical cystectomy-a multi-institutional retrospective study in Japan. (2017)
  • Author(s): Abe T, Takada N, Kikuchi H, Matsumoto R, Osawa T, Murai S, Miyajima N,
  • Journal Title: Jpn J Clin Oncol. Volume: 47 Issue: 8 Pages: 755-761
  • DOI: 10.1093/jjco/hyx062
  • NAID: 120006352214
  • Peer Reviewed / Open Access
• [Journal Article] miR-145 Promoted Anoikis Resistance in Tumor Endothelial Cells. (2017)
  • Author(s): 8.Hida K, Kawamoto T, Maishi N, Morimoto M, Akiyama K, Ohga N, Shindoh M, Shinohara N, Hida Y
  • Journal Title: Journal of biochemistry Volume: 162 Issue: 2 Pages: 81-84
  • DOI: 10.1093/jb/mvx033
  • NAID: 40021299734
  • Peer Reviewed / Open Access
• [Journal Article] Tumor Endothelial Cells with High Aldehyde Dehydrogenase Activity Show drug resistance (2017)
  • Author(s): 9.Hida K, Maishi N, Akiyama K, Ohmura-Kakutani H, Torii C, Ohga N, Osawa T, Kikuchi H, Morimoto H, Morimoto M et al
  • Journal Title: Cancer Sci Volume: 108 Issue: 11 Pages: 2195-2203
  • DOI: 10.1111/cas.13388
  • NAID: 120006373733
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of Medical Adverse Events/Near Misses Associated With Laparoscopic/Thoracoscopic Surgery: A Retrospective Study Based on the Japanese National Database of Medical Adverse Events. (2017)
  • Author(s): Abe T, Murai S, Nasuhara Y, Shinohara N.
  • Journal Title: J Patient Saf. Volume: - Issue: 4 Pages: 343-351
  • DOI: 10.1097/pts.0000000000000422
  • Peer Reviewed / Open Access
• [Journal Article] Active heavy cigarette smoking is associated with poor survival in Japanese patients with advanced renal cell carcinoma: sub-analysis of the multi-institutional national database of the Japanese Urological Association. (2017)
  • Author(s): 12.Hara T, Fujimoto H, Kondo T, Shinohara N, Obara W, Kimura G, Kume H, Nonomura N, Hongo F, Sugiyama T et al
  • Journal Title: Japanese journal of clinical oncology Volume: 47 Issue: 12 Pages: 1162-1169
  • DOI: 10.1093/jjco/hyx129
  • Peer Reviewed / Open Access
• [Journal Article] ATP-binding cassette transporters in tumor endothelial cells and resistance to metronomic chemotherapy (2017)
  • Author(s): Hida Kyoko、Kikuchi Hiroshi、Maishi Nako、Hida Yasuhiro
  • Journal Title: Cancer Letter Volume: 400 Pages: 305-310
  • DOI: 10.1016/j.canlet.2017.02.006
  • Peer Reviewed
• [Journal Article] Tumor endothelial cells accelerate tumor metastasis (2017)
  • Author(s): Maishi Nako、Hida Kyoko
  • Journal Title: Cancer Sci Volume: 108 Issue: 10 Pages: 1921-1926
  • DOI: 10.1111/cas.13336
  • Peer Reviewed
• [Journal Article] ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells (2017)
  • Author(s): Hojo Takayuki、Maishi Nako、Towfik Alam Mohammad、Akiyama Kosuke、Ohga Noritaka、Shindoh Masanobu、Hida Yasuhiro、Minowa Kazuyuki、Fujisawa Toshiaki、Hida Kyoko
  • Journal Title: Oncotarget Volume: 8 Issue: 28 Pages: 45484-45495
  • DOI: 10.18632/oncotarget.17567
  • NAID: 120006344445
  • Peer Reviewed / Open Access
• [Journal Article] Vasohibin-1 as a novel prognostic factor for head and neck squamous cell carcinoma (2017)
  • Author(s): Torii C., Hida Y., Shindoh M., Akiyama K., Ohga N., Maishi N., Ohiro Y., Ono M., Totsuka Y., Kitagawa Y., Tei K., Sato Y., Hida K.
  • Journal Title: Anticancer Res Volume: 37 Issue: 3 Pages: 1219-1225
  • DOI: 10.21873/anticanres.11437
  • Peer Reviewed / Open Access
• [Presentation] Promotion of metastasis via alteration of vascular endothelium by tumor exosome miRNA (2018)
  • Author(s): Morimoto M., Maishi N., Matsuda A., Kitamura T., Higashino F., Yokoyama A., Kitagawa Y., Hida K.
  • Organizer: The 66th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research
• [Presentation] MDR1/ABCB1 upregulation in tumor blood vessels by chemotherapy-induced IL-8 (2018)
  • Author(s): Hida K., Kikuchi H., Maishi N., Abe T., Maruyama S., Harabayashi T., Ameda K., Matsuno Y., Hida Y., Shinohara N.
  • Organizer: 20th International Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer (2018)
  • Author(s): Hida Y., Morimoto H., Maishi N., Nishihara H., Hatanaka Y., Matsuno Y., Nakamura T., Hirano S., Hida K.
  • Organizer: 20th International Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] Tumor endothelial cells survive under lactic acidosis (2018)
  • Author(s): D.A.Annan, Maishi N., Soga T. R.Dawood, Hida Y., Hida K.
  • Organizer: AACR ANNUAL MEETING 2018
  • Int'l Joint Research
• [Presentation] Biglycan, tumor endothelial secreting proteoglycan, as possible biomarker for lung cancer (2018)
  • Author(s): Morimoto H., Maishi N., Hida Y., Nishihara H., Hatanaka Y., Matsuo Y., Nakamura Y., Hirano S., Hida K.
  • Organizer: AACR ANNUAL MEETING 2018
  • Int'l Joint Research
• [Presentation] 高転移性腫瘍エクソソーム による血管内皮の形質変化によってがんの転移が促進される (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，北川善政，樋田京子
  • Organizer: 第26回日本血管生物医学会学術集会
• [Presentation] The involvement of stromal biglycan in tumor angiogenesis and metastasis (2018)
  • Author(s): Li Cong, 間石奈湖，Young Marian F, 森本浩史, 森本真弘，Annan Dorcas A., 樋田泰浩，樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] Carbonic anhydrase 2 (CAⅡ) is essential for tumor endothelial cell proliferation (2018)
  • Author(s): Annan Dorcas A., 間石奈湖，曽我朋義，篠原信雄，Dawood Randa, Li Cong, 菊地 央，北條敬之，森本真弘，樋田泰浩，樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，北川善政, 樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化による転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，樋田京子
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 尿路上皮癌における抗癌剤治療後の腫瘍血管ABCB1発現亢進 (2018)
  • Author(s): 菊地 央，間石奈湖，土屋邦彦，安部崇重，樋田泰浩，原林 透，松野吉弘，篠原信雄，樋田京子
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田京子
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘, 間石奈湖, 北川善政, 樋田京子
  • Organizer: 第27回日本がん転移学会学術集会・総会
• [Presentation] Glutamine Metabolism in Tumor Endothelial Cells (2018)
  • Author(s): Dorcas A. Annan, Maishi N., Soga T., Randa Dawood, Hida Y. and Hida K
  • Organizer: 第107回日本病理学会総会
• [Presentation] MDR1/ABCB1 upregulation in tumor blood vessels by chemotherapy-induced IL-8 (2018)
  • Author(s): Maishi N., Kikuchi H., Abe T., Maruyama S., Harabayashi T., Ameda K., Matsuno Y., Hida Y., Shinohara N., Hida K.
  • Organizer: 第107回日本病理学会総会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進 (2018)
  • Author(s): 森本真弘, 間石奈湖, 菊地 央, 北川善政, 樋田京子
  • Organizer: 第107回日本病理学会総会
• [Presentation] 肺癌症例における腫瘍血管内皮マーカーbiglycanの発現解析 (2018)
  • Author(s): 森本浩史, 間石奈湖, 樋田泰浩, 西原広史, 畑中 豊, 松野吉宏, 中村 透, 平野 聡, 樋田京子
  • Organizer: 第107回日本病理学会総会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘, 間石奈湖, 北川善政, 樋田京子
  • Organizer: 第72回日本口腔科学会学術集会
• [Presentation] 第40回日本分子生物学会年会ワークショップ (2017)
  • Author(s): 間石奈湖
  • Organizer: 「細胞外小胞顆粒は我々に何を語るか？～細胞間コミュニケーションが織りなす生命現象の解明へ～」，“高転移性腫瘍miRによる血管内皮における薬剤耐性誘導”
• [Presentation] “Tumor endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan” (2017)
  • Author(s): 間石奈湖
  • Organizer: 第116回北海道癌談話会奨励賞受賞記念講演
• [Presentation] umor endothelial cells in high metastatic tumors promote metastasis via biglycan, Protein (2017)
  • Author(s): Maishi N., Hida K.
  • Organizer: Island Matsuyama 2017 International Symposium
  • Int'l Joint Research
• [Presentation] Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy (2017)
  • Author(s): 4.Kikuchi H., Maishi N., Akiyama K., Morimoto M., Yanagiya M., Miyajima N., Tsuchiya K., Maruyama S., Abe T., Hida Y., Harabayashi T., Ameda K., Matsumoto R., Kashiwagi A., Matsuno Y., Shinohara N., Hida K.
  • Organizer: ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] 尿路上皮癌における抗癌剤治療後の腫瘍血管ABCB1発現亢進 (2017)
  • Author(s): 6.菊地 央, 間石奈湖, 秋山廣輔, 森本真弘, 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, 松野吉宏, 篠原信雄, 樋田京子
  • Organizer: 第26回日本がん転移学会学術集会
• [Presentation] Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy (2017)
  • Author(s): 7.菊地 央, 間石奈湖, 秋山廣輔, Randa Ibrahim Hassan Dawood, 土屋邦彦, 丸山 覚, 安部崇重, 樋田泰浩，原林 透, 飴田 要, 柏木 明, 松野吉宏, 篠原信雄, 樋田京子
  • Organizer: 第5回がんと代謝研究会 in 札幌