Tanaka, Nobuyuki

写真a

Affiliation

School of Medicine, Department of Urology (Shinanomachi)

Position

Instructor

Academic Background 【 Display / hide

  • 1996.04
    -
    2003.03

    慶應義塾大学, 医学部

    Graduated

 
 

Papers 【 Display / hide

  • TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

    Niwa N., Tanaka N., Hongo H., Miyazaki Y., Takamatsu K., Mizuno R., Kikuchi E., Mikami S., Kosaka T., Oya M.

    Laboratory Investigation (Laboratory Investigation)  99 ( 11 ) 1702 - 1713 2019.11

    ISSN  00236837

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    © 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology. Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

  • Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy

    Kaneko G., Shirotake S., Nishimoto K., Miyazaki Y., Ito K., Ito Y., Hagiwara M., Kanao K., Nakagawa K., Momma T., Asano T., Tanaka N., Mizuno R., Oya M., Oyama M.

    Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology)  49 ( 8 ) 780 - 785 2019.08

    ISSN  03682811

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    © The Author(s) 2019. Published by Oxford University Press. All rights reserved. Background: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

  • BCG-induced cytokine release in bladder cancer cells is regulated by Ca <sup>2+</sup> signaling

    Ibarra C., Karlsson M., Codeluppi S., Varas-Godoy M., Zhang S., Louhivuori L., Mangsbo S., Hosseini A., Soltani N., Kaba R., Kalle Lundgren T., Hosseini A., Tanaka N., Oya M., Wiklund P., Miyakawa A., Uhlén P.

    Molecular Oncology (Molecular Oncology)  13 ( 2 ) 202 - 211 2019.02

    ISSN  15747891

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    © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. Bacillus Calmette–Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca 2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca 2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca 2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

  • Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma

    Ito K., Masunaga A., Tanaka N., Mizuno R., Shirotake S., Yasumizu Y., Ito Y., Miyazaki Y., Hagiwara M., Kanao K., Mikami S., Momma T., Masuda T., Nakagawa K., Oyama M., Asano T., Oya M.

    Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology)  49 ( 1 ) 69 - 76 2019

    ISSN  03682811

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    © The Author(s) 2018. Published by Oxford University Press. All rights reserved. Objectives: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. Methods: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation—including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase—were reviewed. To identify progression-free survival predictors, multivariate analyses were done. Results: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). Conclusions: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

  • The prognostic value of zonal origin and extraprostatic extension of prostate cancer for biochemical recurrence after radical prostatectomy

    Takamatsu K., Matsumoto K., Shojo K., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Shinojima T., Kikuchi E., Asanuma H., Oya M.

    Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations)   2019

    ISSN  10781439

     View Summary

    © 2019 Elsevier Inc. Objective: To investigate the influence of the zonal origin of prostate cancer and extraprostatic extension on biochemical recurrence (BCR). Patients and methods: We included 638 consecutive patients undergoing radical prostatectomy between 2005 and 2015 who did not receive neoadjuvant/adjuvant therapy. The largest lesion was defined as the index tumor. We categorized each patient into the transition zone (TZ) or peripheral zone (PZ) group based on the lesion where the index tumor existed. Differences in the BCR defined as increasing prostate-specific antigen rate between groups were examined by Kaplan-Meier analysis and the Cox proportional hazards model. Results: There were 293 (46%) patients with TZ cancer and 345 (54%) with PZ cancer. TZ cancer was significantly associated with a higher prostate-specific antigen (P = 0.012), lower biopsy positive core rate (P = 0.020), lower pathological Gleason score (P = 0.017), lower pathological stage (P = 0.002), and lower rate of seminal vesicle invasion (P = 0.002). During a median follow-up period of 59 months, 79 patients (12%) developed BCR. In the entire cohort, the PZ origin (hazard ratio: 1.68, P = 0.033) and extraprostatic extension were independent risk factors for BCR. The 3-, 5-, and 7-year BCR-free survival rates of patients with pT3a TZ cancer were 89%, 88%, and 86%, respectively, which were significantly better than those of patients with pT3a PZ cancer (80%, 74%, and 62%, P = 0.012), but were similar to those of the pT2 cancer cohort (92%, 91%, and 90%, P = 0.376). Conclusion: TZ cancer had more favorable pathological characteristics and oncological outcome than PZ cancer especially in pT3a cases.

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Papers, etc., Registered in KOARA 【 Display / hide

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Presentations 【 Display / hide

  • 3次元ライトシート顕微鏡による泌尿器癌微小環境の可視化: 組織透明化の新規プロトコールと臨床応用

    第107回日本泌尿器科学会総会, 2019.04

  • Transcription and protein phenotyping with 3D pathology: Light-sheet microscopy overlooks cellular malignancy of intact tumour volumes

    TANAKA NOBUYUKI

    European Association of Urology 2019 Annual Meeting, 2019.03, Poster (general)

  • がん微小環境の可視化:透明化技術を利用した次世代癌イメージング

    第83回日本泌尿器科学会東部総会, 2018.10, Symposium, Workshop, Panelist (nomination)

  • Light-sheet microscopy: Diagnosing intratumoral heterogeneity of intact tumors in three-dimension.

    TANAKA NOBUYUKI

    European Association of Urology 2018 Annual Meeting, 2018.03, Poster (general)

  • CHARACTERISTICS AND OUTCOME IN METASTATIC UPPER TRACT UROTHELIAL CARCINOMA FOLLOWING RADICAL NEPHROURETERECTOMY: THE MULTI-INSTITUTIONAL EXPERIENCE

    Tanaka, Nobuyuki

    JOURNAL OF UROLOGY, 2013.04, Oral Presentation(general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 腎癌幹細胞ニッチを掌握する解析基盤の構築とがん組織不均一性の理解

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, 基盤研究(B), Principal Investigator

  • 腫瘍内不均一性を可視化する次世代癌イメージングを用いた薬剤感受性の予測モデル構築

    2018.06
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, Grant-in-Aid for Challenging Research (Exploratory) , Principal Investigator

  • 腎細胞癌の免疫環境と血管新生阻害後のリモデリングの統合的解析による新規治療の開発

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 大家 基嗣, 基盤研究(B), Co-investigator

  • シングルセルレベルの腫瘍内不均一性をターゲットとする革新的な創薬研究

    2018.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, Grant-in-Aid for Scientific Research on Innovative Areas, Principal Investigator

  • Tumor microenvironment and ubiquitin system in platinum resistance urothelial carcinoma

    2014.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 田中 伸之, Grant-in-Aid for Scientific Research (C), Principal Investigator

     View Summary

    To identify the molecules involved in epithelial-to-mesenchymal transition (EMT) in tumors post acquired platinum resistance (PR), we examined the changes in gene expression before and after platinum treatment. Four urothelial carcinoma cell lines, T24, 5637, and their PR sublines of T24PR and 5637PR, were assessed by microarray, and FBXO32 was newly identified as a negative regulator of EMT. In vitro study showed an intimate relationship between FBXO32 expression and EMT, demonstrating that FBXO32 knockdown resulted in the EMT acquisition. In contract, FBXO32 overexpression suppressed EMT. The association between FBXO32 expression and EMT was further validated using human specimens. CGH array analysis demonstrated loss of heterozygosity at 8q24.13 in T24PR cells, which harbors FBXO32. In 5637PR cells, decreased nuclear FOXO1/3a expression seemed to affect FBXO32 dysregulation. These results suggest the association between EMT and ubiquitin-proteasome regulation when tumors develop PR.

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Awards 【 Display / hide

  • 第107回日本泌尿器科学会総会総会総会賞(ビデオ:副腎・腎・尿管・その他)

    2019

  • “Best poster nomination”, The 34th Annual Congress of the European Association of Urology

    2019

  • 日本泌尿器科学会学会賞(基礎)

    2018

  • 慶應義塾大学医学部三四会奨励賞(基礎医学)

    2018

  • 公益財団法人武田科学振興財団医学系研究継続助成

    2017

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Courses Taught 【 Display / hide

  • LECTURE SERIES, UROLOGY

    2019