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

• Project/Area Number: 15K10605
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Nara Medical University
• Principal Investigator: FUJIMOTO KIYOHIDE 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
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 膀胱癌 / 上皮内癌 / 膀胱内注入療法 / CLDN / CXCL1 / Collagen / CD56 / 制御性T細胞 / 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 / 腫瘍微小環境 / 膀胱上皮内癌 / DNAメチル化 / 上皮間葉転換 / 血管新生因子 / 免疫応答

Outline of Final Research Achievements

Expression of OCT3/4 and CXCL1 is associated with BCG treatment failure of carcinoma in situ of the urinary bladder. Induction of CD4+、CD8+、CD56+、CD204+、Foxp3+ immune cells is also associated with BCG treatment outcomes of non-muscle invasive bladder cancer including carcinoma in situ. CLDN4 expression of cancer cells and CXCL1 in the tumor microenvironment is associated with recurrence, progression and drug resistance. Collagen type Ⅵα1 and collagen type ⅩⅢα1 expression in tumor budding site is associated with muscle invasion. A biomarker panel including IL8、MMP9、MMP10、angiogenin A、APOE、SDC1、A1AT、PAⅡ、CA9、and VEGF is a useful tool for predicting muscle invasive progression of carcinoma in situ.

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 Issue: 28 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: - Issue: 7 Pages: 1557-1563
  • 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 Issue: 5 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 Issue: 4 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 Issue: 10 Pages: 2186-2186
  • 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 Issue: 11 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 Issue: 11 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 Issue: 22 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 Issue: 4 Pages: e0175494-e0175494
  • DOI: 10.1371/journal.pone.0175494
  • Peer Reviewed / Open Access
• [Journal Article] Expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer (2016)
  • Author(s): Yasushi Nakai, Yoshihiro Tatsumi, Makito Miyake, Satoshi Anai, Masaomi Kuwada, Sayuri Onishi, Yoshitomo Chihara, Nobumichi Tanaka, Yoshihiko Hirao, Kiyohide Fujimoto
  • Journal Title: Photodiagnosis and Photodynamic Therapy Volume: 13 Pages: 225-232
  • DOI: 10.1016/j.pdpdt.2015.07.174
  • Peer Reviewed / Open Access
• [Journal Article] A multiplex urinary immunoassay for bladder cancer detection: analysis of a Japanese cohort. (2016)
  • Author(s): Goodison S, Ogawa O, Matsui Y, Kobayashi T, Miyake M, Ohnishi S, Fujimoto K, Dai Y, Shimizu Y, Tsukikawa K, Furuya H, Rosser CJ.
  • Journal Title: J Transl Med Volume: 14 Pages: 287-287
  • NAID: 120006318862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer. (2016)
  • Author(s): Miyake M, Hori S, Morizawa Y, Tatsumi Y, Nakai Y, Anai S, Torimoto K, Aoki K, Tanaka N, Shimada K, Konishi N, Toritsuka M, Kishimoto T, Rosser CJ, Fujimoto K.
  • Journal Title: Neoplasia Volume: 18 Issue: 10 Pages: 636-646
  • DOI: 10.1016/j.neo.2016.08.002
  • Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clinical significance of alpha- and beta-Klotho in urothelial carcinoma of the bladder (2016)
  • Author(s): Shunta Hori, Makito Miyake, Sayuri Onishi, Yoshihiro Tatsumi, Yosuke Morizawa, Yasushi Nakai, Satoshi Anai, Nobumichi Tanaka, and Kiyohide Fujimoto
  • Journal Title: Oncology Reports Volume: 未定
  • Peer Reviewed / Open Access
• [Journal Article] Neutrophil to lymphocyte ratio as a detection marker of tumor recurrence in patients with muscle-invasive bladder cancer after radical cystectomy (2016)
  • Author(s): Morizawa Y, Miyake M, Shimada K, Hori S, Tatsumi Y, Nakai Y, Anai S, Tanaka N, Konishi N, Fujimoto K
  • Journal Title: Urol Oncol Volume: 257 Issue: 6 Pages: 257.e11-257.e17
  • DOI: 10.1016/j.urolonc.2016.02.012
  • Peer Reviewed / Open Access
• [Journal Article] Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer (2015)
  • Author(s): Masaomi Kuwada, Yoshitomo Chihara, Yi Luo, Xiangru Li, Yukiko Nishiguchi, Rina Fujiwara, Takamistu Sasaki, Kiyomu Fujii, Hitoshi Ohmori, Kiyohide Fujimoto, Masuo Kondoh, Hiroki Kuniyasu
  • Journal Title: Cancer Letters Volume: 369 Issue: 1 Pages: 212-221
  • DOI: 10.1016/j.canlet.2015.08.019
  • 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] 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
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2017-03-24
  • Int'l Joint Research
• [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
• [Presentation] CD204, G-CSF, GM-CSF and PD-L1 expression in muscle invasive bladder cancer (2016)
  • Author(s): Morizawa Y, Miyake M, Onishi K, Hori S, Tatsumi Y, Nakai Y, Anai S, Tanaka N, Fujimoto K
  • Organizer: 36th Congress of the Société Internationale d'Urologie
  • Place of Presentation: Buenos Aires, Argentina
  • Year and Date: 2016-10-20
  • Int'l Joint Research
• [Presentation] Klothoは脈管侵襲能を促進し膀胱癌進展に寄与する (2016)
  • Author(s): 堀 俊太、三宅牧人、辰巳佳弘、森澤洋介、中井 靖、田中宣道、藤本清秀
  • Organizer: 第25回泌尿器科分子・細胞研究会
  • Place of Presentation: ハイアットリージェンシー大阪
  • Year and Date: 2016-02-26
• [Presentation] Claudine-4 細胞外ドメインを認識するモノクロナル抗体による膀胱癌の分子標的療法の検討 (2015)
  • Author(s): 桑田真臣、羅 奕、李 相儒、西口由希子、藤原里奈、佐々木隆光、千原良友、藤本清秀、近藤昌夫、國安弘基
  • Organizer: 第24回日本がん転移学会学術集会・総会
  • Place of Presentation: シティプラザ大阪
  • Year and Date: 2015-07-23