Molecular biological profile of carcinoma in situ of urinary bladder as predictive and prognostic markers

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K10605
• Research Institution: Nara Medical University
• Principal Investigator: 藤本 清秀 奈良県立医科大学, 医学部, 教授 (50264867)
• Co-Investigator(Kenkyū-buntansha): 千原 良友 奈良県立医科大学, 医学部附属病院, 研究員 (40405395) ; 三宅 牧人 奈良県立医科大学, 医学部, 研究員 (80601400)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 膀胱がん / 免疫細胞 / ミトコンドリア / アミノレブリン酸 / BCG / コラーゲン / 鉄 / がん微小環境

Outline of Annual Research Achievements

ヒト膀胱がん組織とマウス化学発がんモデルを用いて、筋層非浸潤性膀胱がんや上皮内癌の発育進展に関連する分子と抗癌剤やBCG膀胱内注入療法に対する治療抵抗性に関連するマーカーを同定した。膀胱がんのがん微小環境においてCXCL1が介在する反応によりTumor-associated macrophages とCancer-associated fibroblastsが腫瘍進展に誘導され関与することを示した。また膀胱がんが産生するcollagen type Ⅳα1とcollagen type ⅩⅢα1が、がんの浸潤ポイントにおいてtumor buddingを誘導することを確認した。BCG膀胱内注入療法では、CD4、CD8、CD56陽性細胞が誘導されるが、CD204、制御性 T 細胞、PD-L1陽性細胞は抑制されず、抗癌剤ではCD56、CD204、Foxp3陽性細胞が抑制されることを明らかにした。一方、BCGはIL1A、ILl2、IL17Aを誘導し、抗癌剤はIL4、IL17Aを誘導するなど、薬剤により誘導する免疫応答が異なることを確認した。がん細胞のミトコンドリア内の鉄代謝異常を解析し、5-aminolevulinic acid、protoporphirin Ⅸ、鉄イオン、活性酸素種、p53、ferrochelatase、heme　oxygenase-1、peptide transporter-1、ATP-binding cassete group-2、hydroxymethilbilane synthaseなどの鉄代謝関連物質の動態を解析し、鉄の蓄積が活性酸素種の増加を起こし、発がんや進展に関与することを明らかにした。Ferrochelatase発現低下がヘム合成経路におけるprotoporphirin Ⅸの蓄積に関係すること、p53がミトコンドリア内の鉄代謝関連蛋白を制御する。

Research Products

• [Journal Article] Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer. (2018)
  • Author(s): Hori S, Miyake M, Tatsumi Y, Morizawa Y, Nakai Y, Onishi S, Onishi K, Iida K, Gotoh D, Tanaka N, Fujimoto K.
  • Journal Title: Oncotarget Volume: 9 Pages: 19508-19524
  • DOI: 10.18632/oncotarget.24628
  • Peer Reviewed / Open Access
• [Journal Article] Spectrophotometric photodynamic diagnosis of prostate cancer cells excreted in voided urine using 5-aminolevulinic acid. (2018)
  • Author(s): Nakai Y, Miyake M, Anai S, Hori S, Tatsumi Y, Morizawa Y, Onisi S, Tanaka N, Fujimoto K.
  • Journal Title: Lasers Med Sci. Volume: - Pages: -
  • DOI: 10.1007/s10103-018-2519-4.
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin after radical nephroureterectomy for upper urinary tract urothelial carcinoma. (2018)
  • Author(s): Miyake M, Tatsumi Y, Matsumoto H, Nagao K, Matsuyama H, Inamoto T, Azuma H, Yasumoto H, Shiina H, Fujimoto K; Nishinihon Uro-Oncology Collaborative Group.
  • Journal Title: BJU Int. Volume: 121 Pages: 764-773
  • DOI: 10.1111/bju.14111.
  • Peer Reviewed / Open Access
• [Journal Article] Biological Behavior and Long-Term Outcomes of Carcinoma In Situ in Upper Urinary Tract Managed by Radical Nephroureterectomy. (2018)
  • Author(s): Inamoto T, Matsuyama H, Ibuki N, Komura K, Takahara K, Fujimoto K, Shiina H, Sakano S, Nagao K, Miyake M, Tatsumi Y, Yasumoto H, Azuma H; Nishinihon Uro-Oncology Collaborative Group.
  • Journal Title: J Urol. Volume: 199 Pages: 933-939
  • DOI: 10.1016/j.juro.2017.10.019.
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in Non-Muscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Guérin: A Long-Term Follow-Up Study of a Japanese Cohort. (2017)
  • Author(s): Miyake M, Tatsumi Y, Gotoh D, Ohnishi S, Owari T, Iida K, Ohnishi K, Hori S, Morizawa Y, Itami Y, Nakai Y, Inoue T, Anai S, Torimoto K, Aoki K, Shimada K, Konishi N, Tanaka N, Fujimoto K.
  • Journal Title: Int J Mol Sci. Volume: 18 Pages: -
  • DOI: 10.3390/ijms18102186.
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic and prognostic role of urinary collagens in primary human bladder cancer. (2017)
  • Author(s): Miyake M, Morizawa Y, Hori S, Tatsumi Y, Onishi S, Owari T, Iida K, Onishi K, Gotoh D, Nakai Y, Anai S, Chihara Y, Torimoto K, Aoki K, Tanaka N, Shimada K, Konishi N, Fujimoto K.
  • Journal Title: Cancer Sci. Volume: 108 Pages: 2221-2228
  • DOI: 10.1111/cas.13384.
  • Peer Reviewed / Open Access
• [Journal Article] Spectrophotometric photodynamic detection involving extracorporeal treatment with hexaminolevulinate for bladder cancer cells in voided urine. (2017)
  • Author(s): Nakai Y, Ozawa T, Mizuno F, Onishi S, Owari T, Hori S, Morizawa Y, Tatsumi Y, Miyake M, Tanaka N, Tsuruta D, Fujimoto K.
  • Journal Title: J Cancer Res Clin Oncol. Volume: 143 Pages: 2309-2316
  • DOI: 10.1007/s00432-017-2476-5.
  • Peer Reviewed / Open Access
• [Journal Article] Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder. (2017)
  • Author(s): Miyake M, Hori S, Morizawa Y, Tatsumi Y, Toritsuka M, Ohnishi S, Shimada K, Furuya H, Khadka VS, Deng Y, Ohnishi K, Iida K, Gotoh D, Nakai Y, Inoue T, Anai S, Torimoto K, Aoki K, Tanaka N, Konishi N, Fujimoto K.
  • Journal Title: Oncotarget Volume: 8 Pages: 36099-36114
  • DOI: 10.18632/oncotarget.16432.
  • Peer Reviewed / Open Access
• [Journal Article] Topical and systemic immunoreaction triggered by intravesical chemotherapy in an N-butyl-N-(4-hydroxybutyl) nitorosamine induced bladder cancer mouse model. (2017)
  • Author(s): Hori S, Miyake M, Tatsumi Y, Onishi S, Morizawa Y, Nakai Y, Tanaka N, Fujimoto K.
  • Journal Title: PLoS One Volume: 12 Pages: e0175494
  • DOI: 10.1371/journal.pone.0175494.
  • Peer Reviewed / Open Access
• [Presentation] Altered deposition of collagens promote tumor budding at the tumor invasion front in urothelial carcinoma of the bladder (2018)
  • Author(s): Miyake M, Hori S, Morizawa Y, Nakai Y, Owari T, Itami Y, Tanaka N, Fujimoto K
  • Organizer: 33rd Annual European Association of Urology Congress
  • Int'l Joint Research
• [Presentation] Intravesical instillation of chemotherapeutic agents enhances immunomodulation of tumor microenvironment status in conventional BCG therapy (2018)
  • Author(s): Hori S, Miyake M, Tatsumi Y, Morizawa Y, Nakai Y, Onishi K, Iida K, Gotoh D, Itami Y, Tanaka N, Fujimoto K
  • Organizer: 33rd Annual European Association of Urology Congress
• [Presentation] Clinical Significance of Gamma-Klotho in Urothelial Carcinoma of the Bladder (2017)
  • Author(s): Hori S, Miyake M, Morizawa Y, Tatsumi Y, Nakai Y, Fujimoto K
  • Organizer: 37th Congress of the Société Internationale d'Urologie
  • Int'l Joint Research
• [Presentation] Evaluation of pro-and anti-tumor effect induced by three colony-stimulating factors, G-CSF/GM-CSF/M-CSF using a human bladder cancer xenograft model: Is G-CSF a friend of cancer cells? (2017)
  • Author(s): Hori S, Miyake M, Tatsumi Y, Morizawa Y, Nakai Y, Goto D, Onishi K, Iida K, Onishi S, Tanaka N, Fujimoto K
  • Organizer: 32th Annual European Association of Urology Congress
  • Int'l Joint Research
• [Presentation] Deposition of type IV and XIII collagens promote tumor infiltration at the invasion front in human bladder cancer (2017)
  • Author(s): Miyake M, Hori S, Morizawa Y, Toritsuka M, Tatsumi Y, Nakai Y, Anai S, Tanaka N, Shimada K, Fujimoto K
  • Organizer: 32th Annual European Association of Urology Congress