Molecular mechanism of bladder cancer invasion and metastasis focusing on invadopodia, exosome, and hyaluronidase

• Project/Area Number: 18K16720
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Hirosaki University
• Principal Investigator: Tokui Noriko 弘前大学, 医学研究科, 客員研究員 (00792342)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 膀胱癌 / エキソソーム / Cortactin / 尿路上皮癌 / エクソソーム / コータクチン / 転移 / 浸潤 / 浸潤突起

Outline of Final Research Achievements

In this study, we focused on a novel hyaluronan-degrading enzyme (TMEM2) in exosomes secreted by invasive processes of bladder cancer cell lines and Cortactin, a molecule important for invasive processes, to examine the mechanism of invasion and metastasis of bladder cancer. Cellular experiments suggested that the formation of invasive processes by Cortactin is essential for exosome secretion. In mouse experiments, exosome pretreatment did not increase lung metastasis. There was no difference in integrin expression in clinical specimens between healthy subjects and bladder cancer patients, and no difference in TMEM2 expression in exosomes between healthy subjects and bladder cancer patients.

Academic Significance and Societal Importance of the Research Achievements

本研究から、エキソソームの分泌にはCortactinによって形成される浸潤突起の形成が必須であることが示された。浸潤突起とエキソソームには共通の機序があるため、エキソソームが関与する転移抑制のターゲットになりうる分子として可能性が示唆さ、学術的意義や社会的意義は大きいと思われる。また、エキソソームが転移の前段階を調整する機序や臨床サンプルでのインテグリン、TMEM2の差は見られなかったが、これら分子をエキソソームで検討した初の研究であり、本研究成果の意義は大きいと思われる。

Research Products

• [Journal Article] Trends in the use of neoadjuvant chemotherapy and oncological outcomes for high‐risk upper tract urothelial carcinoma: a multicentre retrospective study (2021)
  • Author(s): Hamaya Tomoko、Hatakeyama Shingo、Tanaka Toshikazu、Kubota Yuka、Togashi Kyo、Hosogoe Shogo、Fujita Naoki、Kusaka Ayumu、Tokui Noriko、Okamoto Teppei、Yamamoto Hayato、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: BJU International Volume: - Issue: 4 Pages: 468-476
  • DOI: 10.1111/bju.15346
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of first‐line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study (2020)
  • Author(s): Tanaka Toshikazu、Hatakeyama Shingo、Numakura Kazuyuki、Kido Koichi、Noro Daisuke、Oikawa Masaaki、Hosogoe Shogo、Tokui Noriko、Yamamoto Hayato、Narita Shintaro、Ito Hiroyuki、Yoneyama Takahiro、Hashimoto Yasuhiro、Kawaguchi Toshiaki、Habuchi Tomonori、Ohyama Chikara
  • Journal Title: International Journal of Urology Volume: 27 Issue: 12 Pages: 1095-1100
  • DOI: 10.1111/iju.14363
  • Peer Reviewed
• [Journal Article] Validation of the IMDC Prognostic Model in Patients With Metastatic Renal-Cell Carcinoma Treated With First-Line Axitinib: A Multicenter Retrospective Study (2019)
  • Author(s): Konishi Sakae、Hatakeyama Shingo、Numakura Kazuyuki、Narita Shintaro、Inoue Takamitsu、Saito Mitsuru、Tokui Noriko、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Yoshikawa Kazuaki、Narita Satoshi、Kawaguchi Toshiaki、Habuchi Tomonori、Ohyama Chikara
  • Journal Title: Clinical Genitourinary Cancer Volume: 17 Issue: 5 Pages: 1080-1089
  • DOI: 10.1016/j.clgc.2019.07.006
  • Peer Reviewed
• [Journal Article] The Impact of Preoperative Severe Renal Insufficiency on Poor Postsurgical Oncological Prognosis in Patients with Urothelial Carcinoma. (2018)
  • Author(s): Momota M, Hatakeyama S, Tokui N, Sato T, Yamamoto H, Tobisawa Y, Yoneyama T, Yoneyama T, Hashimoto Y, Koie T, Narita S, Kawaguchi T, Ohyama C
  • Journal Title: Eur Urol Focus. Volume: 掲載確定・印刷中 Issue: 6 Pages: 001-001
  • DOI: 10.1016/j.euf.2018.03.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of bacillus Calmette-Guerin therapy of upper urinary tract carcinoma in situ: comparison of oncological outcomes with radical nephroureterectomy. (2018)
  • Author(s): Horiguchi H, Yoneyama T, Hatakeyama S, Tokui N, Sato T, Fujita N, Yamamoto H, Tobisawa Y, Yoneyama T, Hashimoto Y, Koie T, Yoshikawa K, Narita S, Kawaguchi T, Ohyama C
  • Journal Title: Med Oncol. Volume: 35 Issue: 4 Pages: 41-41
  • DOI: 10.1007/s12032-018-1102-y
  • Peer Reviewed / Open Access / Int'l Joint Research