Elucidation of molecular targets based on epithelial-mesenchymal transition for the treatment of renal cell carcinoma

• Project/Area Number: 24390374
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Keio University
• Principal Investigator: OYA Mototsugu 慶應義塾大学, 医学部, 教授 (00213885)
• Co-Investigator(Kenkyū-buntansha): MIKAMI Shuji 慶應義塾大学, 医学部, 講師 (20338180) ; KIKUCHI Eiji 慶應義塾大学, 医学部, 講師 (10286552) ; NAKAGAWA Ken 東京歯科大学, 歯学部, 教授 (50227740) ; MIZUNO Ryuichi 慶應義塾大学, 医学部, 講師 (60383824) ; ASANUMA Hiroshi 慶應義塾大学, 医学部, 講師 (70245570) ; MIYAJIMA Akira 慶應義塾大学, 医学部, 准教授 (90245572) ; NAGATA Hirohiko 慶應義塾大学, 医学部, 研究員 (90265900)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 腎細胞癌 / 分子標的治療 / 薬剤耐性 / CD44 / mTOR

Outline of Final Research Achievements

Molecular targeted agents are widely used and better survival benefits are shown for the treatment of metastatic renal cell carcinoma (RCC). However, there are still hurdles to conquer RCC because survival cancer cells survive. The phenotype survival cancer cells look like sarcoma suggesting epithelial- mesenchymal transition. We found out that CD44 is up-regulated in the cells where Tumor Necrosis Factor (TNF)-α　induces the expression.

Research Products

• [Journal Article] Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas. (2015)
  • Author(s): Mikami S, Mizuno R, Kosaka T, Saya H, Oya M and Okada Y
  • Journal Title: Int J Cancer Volume: 136 Pages: 1504-1514
  • DOI: 10.1002/ijc.29137
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. (2015)
  • Author(s): Ishida M, Mikami S, Shinojima T, Kosaka T, Mizuno R, Kikuchi E, Miyajima A, Okada Y, Oya M
  • Journal Title: Int J Cancer Volume: Epub ahead of print Pages: 299-310
  • DOI: 10.1002/ijc.29398
  • Peer Reviewed / Open Access
• [Journal Article] Invasion and metastasis of renal cell carcinoma. (2014)
  • Author(s): Mikami S, Oya M, Mizuno R, Kosaka T, Katsube KI, Okada Y
  • Journal Title: Med Mol Morphol Volume: 47(2) Pages: 63-7
  • DOI: 10.1007/s00795-013-0064-6
  • Peer Reviewed
• [Journal Article] The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy : A Multi-institutional Study (2014)
  • Author(s): Tanaka N, Kikuchi E, Shirotake S, Kanao K, Matsumoto K, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Ito Y, Kosaka T, Kodaira K, Oyama M, Miyajima A, Momma T, Nakagawa K, Ueno M, Oya M
  • Journal Title: European Urology Volume: 65(1) Pages: 227-234
  • DOI: 10.1016/j.eururo.2012.11.050
  • Peer Reviewed
• [Journal Article] Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Hagiwara M, Kosaka T, Oyama M, Miyajima A, Momma T, Nakagawa K, Jinzaki M, Hasegawa S, Nakajima Y, Oya M
  • Journal Title: Ann Surg Oncol Volume: 21(9) Pages: 3151-8
  • DOI: 10.1245/s10434-014-3657-y
  • Peer Reviewed
• [Journal Article] Metastatic Behavior of Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy : Association with Primary Tumor Location (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Kobayashi H, Ide H, Miyazaki Y, Obata J, Hoshino K, Shirotake S, Akita H, Kosaka T, Miyajima A, Momma T, Nakagawa K, Hasegawa S, Nakajima Y, Jinzaki M, Oya M
  • Journal Title: Annals of Surgical Oncology Volume: 21(3) Pages: 1038-1045
  • DOI: 10.1245/s10434-013-3349-z
  • Peer Reviewed
• [Journal Article] The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma : A multi-institutional study (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Kobayashi H, Miyazaki Y, Ide H, Obata J, Hoshino K, Hayakawa N, Kosaka T, Oyama M, Miyajima A, Momma T, Nakagawa K, Jinzaki M, Nakajima Y, Oya M
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 32(1)
  • DOI: 10.1016/j.urolonc.2013.07.003
  • Peer Reviewed
• [Journal Article] A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy. (2014)
  • Author(s): Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Miyazaki Y, Kobayashi H, Kaneko G, Hagiwara M, Ide H, Obata J, Hoshino K, Hayakawa N, Kosaka T, Hara S, Oyama M, Momma T, Nakajima Y, Jinzaki M, Oya M
  • Journal Title: Annals of Surgical Oncology Volume: 21(12) Pages: 4041-4048
  • DOI: 10.1245/s10434-014-3830-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma. (2014)
  • Author(s): Kaneko G, Miyajima A, Yuge K, Yazawa S, Mizuno R, Kikuchi E, Jinzaki M, Oya M
  • Journal Title: Jpn J Clin Oncol Volume: 45(2) Pages: 210-6
  • DOI: 10.1093/jjco/hyu193
  • Peer Reviewed
• [Journal Article] Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib. (2014)
  • Author(s): Kondo T, Nakazawa H, Oya M, Kimura G, Fujii Y, Hatano T, Kawata N, Kume H, Morita M, Nakajima K, Ohno Y, Okegawa T, Takahashi S, Wakumoto Y, Horie S
  • Journal Title: Jpn J Clin Oncol Volume: 45(3) Pages: 274-80
  • DOI: 10.1093/jjco/hyu200
  • Peer Reviewed
• [Journal Article] Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high-risk patients with upper tract urothelial carcinoma: A Japanese multi-institution experience. (2014)
  • Author(s): Shirotake S, Kikuchi E, Tanaka N, Matsumoto K, Miyazaki Y, Kobayashi H, Ide H, Obata J, Hoshino K, Kaneko G, Hagiwara M, Kosaka T, Kanao K, Kodaira K, Hara S, Oyama M, Momma T, Miyajima A, Nakagawa K, Hasegawa S, Nakajima Y, Oya M
  • Journal Title: J Urol Volume: 193(4) Pages: 1122-8
  • DOI: 10.1016/j.juro.2014.10.022
  • Peer Reviewed
• [Journal Article] Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor. (2014)
  • Author(s): Mizuno R, Miyajima A, Oya M.
  • Journal Title: Int J Urol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Renal angiomyolipoma: a radiological classification and update on recent developments in diagnosis and management. (2014)
  • Author(s): Jinzaki M, Silverman SG, Akita H, Nagashima Y, Mikami S,Oya M.
  • Journal Title: Abdom Imaging. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Renal cell carcinoma in patients with acquired cystic disease of the kidney:Assessment using a combination of T2-weighted, diffusion-weighted, and chemical-shift MRI without the use of contrast material. (2014)
  • Author(s): Akita H, Jinzaki M, Akita A, Mikami S, Oya M, Kuribayashi S.
  • Journal Title: J Magn Reson Imaging Volume: 39(4) Pages: 924-30
  • DOI: 10.1002/jmri.24226
  • Peer Reviewed
• [Journal Article] Invasion and metastasis of renal cell carcinoma. (2013)
  • Author(s): Mikami S, Oya M, Mizuno R, Kosaka T, Katsube KI, Okada Y.
  • Journal Title: Med Mol Morphol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells (2013)
  • Author(s): K. Suzuki, R. Mizuno, K. Suenaga, T. Teruya, N. Tanaka, T. Kosaka, M. Oya
  • Journal Title: Cancer Med Volume: 2 Pages: 32-39
  • DOI: 10.1002/cam4.53
  • Peer Reviewed
• [Journal Article] Effect of a novel nuclear factor-кB activation inhibitor on renal ischemia-reperfusion injury. (2013)
  • Author(s): Kono H, Nakagawa K, Morita S, Shinoda K, Mizuno R, Kikuchi E, Miyajima A, Umezawa K, Oya M.
  • Journal Title: Transplantation. Volume: 96(10) Pages: 863-70
  • DOI: 10.1097/tp.0b013e3182a3df74
  • Peer Reviewed
• [Journal Article] Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma. (2012)
  • Author(s): Mizuno R, Asano K, Oya M, et al.
  • Journal Title: Jpn J Clin Oncol Volume: 42(5) Pages: 442-446
  • Peer Reviewed
• [Journal Article] Prognostic significance of high nuclear grade in patients with pathologic T1a renal cell carcinoma. (2012)
  • Author(s): Suzuki K, Mizuno R, Oya M, et al.
  • Journal Title: Jpn J Clin Oncol Volume: 42(9) Pages: 831-835
  • Peer Reviewed
• [Journal Article] Visceral obesity is a strong predictor of perioperative outcome in patients undergoing laparoscopic radical nephrectomy. (2012)
  • Author(s): Hagiwara M, Miyajima A, Oya M, et al.
  • Journal Title: BJU Int Volume: 110
  • Peer Reviewed
• [Journal Article] The benefit of laparoscopic partial nephrectomy in high body mass index patients. (2012)
  • Author(s): Kaneko G, Miyajima A, Oya M, et al.
  • Journal Title: Jpn J Clin Oncol Volume: 42(7) Pages: 619-624
  • Peer Reviewed
• [Presentation] Efficacy of axitinib in patients with metastatic renal cell carcinoma previously treated with both VEGFR-TKI and mTORI. (2014)
  • Author(s): Mizuno R , Kosaka T, Mikami S, Oya M
  • Organizer: 2014 ASCO Annual Meeting
  • Place of Presentation: Chicago, The United States of America
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Dose adjustment of axitinib based on AUC monitoring in sunitinib-refractory advanced renal cell carcinoma. (2014)
  • Author(s): Miura Y, Chiyo K, Imamura, Uchino K, Kishida T, Matsubara N, Shinojima T, Oya M, Nakaigawa N, Yoshimura K, Takano T, Tanigawara Y
  • Organizer: 2014 ASCO Annual Meeting
  • Place of Presentation: Chicago, The United States of America
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Increased expression of aryl hydrocarbon receptor in clear cell renal cell carcinoma and infiltrating lymphocytes: Implications for cancer invasion, prognosis and tumor immunity. (2014)
  • Author(s): Ishida M, Mikami S, Kosaka T, Mizuno R, Kikuchi E, Miyajima A, Nakagawa K, Okada Y, Oya M
  • Organizer: AUA2014 Annual Meeting
  • Place of Presentation: Orlando,The United States of America
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Prognostic significance of TNF-α and CD44 expression in crear cell renal cell carcinomas: implication of cancer invasion, metastasis, and resistance to sunitinib treatment. (2014)
  • Author(s): Mikami S, Mizuno R, Kosaka T, Saya H, Oya M, Okada Y
  • Organizer: AUA2014 Annual Meeting
  • Place of Presentation: Orlando, The United States of America
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Visceral obesity is a useful predictor of better recurrence-free survival after curative surgeries for Japanese patients with localized clear cell renal cell carcinoma. (2014)
  • Author(s): Kaneko G, Miyajima A, Hasegawa R, Mizuno R, Uchida Y, Hara S, Kikuchi E, Nakagawa K, Jinzaki M, Oya M
  • Organizer: 29th Annual EAU Congress
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-04-11 – 2014-04-15
• [Presentation] mTOR pathway regulates the expression of angiotensin 2 type 1 receptor in renal cell carcinoma (2013)
  • Author(s): Kaneko G, Miyajima A, Kosaka T, Mizuno R, Kikuchi E, Oya M.
  • Organizer: The 108th American Urological Association Annual Meeting
  • Place of Presentation: San Diego
• [Presentation] Clinical Experience of Xp11.2 Translocation Renal Cell Carcinoma (2013)
  • Author(s): Mizuno R, Asanuma H, Kono H, Shinojima T, Kikuchi E, Miyajima A, Nakagawa K, Oya M, Mikami S.
  • Organizer: 33rd CONGRESS OF THE SOCIETE INTERNATIONALE D'UROLOGIE
  • Place of Presentation: VANCOUVER
• [Presentation] C-REACTIVE protein indepently predicts the prognosis of patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: A multiinstitutional study. (2013)
  • Author(s): Obata J, Kikuchi E, Tanaka N, Ishioka K, Shirotake S, Matsumoto K, Kobayashi H, Miyazaki Y, Ide H, Hayakawa N, Ito Y, Kanao K, Miyajima A, Momma T, Nakagawa K, Ueno M, Oya M.
  • Organizer: The 108th American Urological Association Annual Meeting.
  • Place of Presentation: San Diego
• [Presentation] Tumor necrosis factoralpha induces epithelial-mesenchymal transition and expression of CD44 in renal cell carcinoma : implications for cancer invasion, metastasis and resistance to the sunitinib treatment (2012)
  • Author(s): Oya M, Mikami S, Mizuno R, et al.
  • Organizer: 28th Annual Urological Research Society Meeting
  • Place of Presentation: 大阪
  • Year and Date: 2012-10-04
• [Presentation] Long-term outcomes of children with Xp11.2 translocation renal cell carcinoma. (2012)
  • Author(s): Asanuma H, Mizuno R, Oya M, et al.
  • Organizer: ASCO Annual Meeting
  • Place of Presentation: Chicago
  • Year and Date: 2012-06-03
• [Presentation] Bisebromoamide, as a novel molecular target drug inhibiting phosphorylation of both extracellular signal-regulated kinase and akt in renal cell carcinoma. (2012)
  • Author(s): Suzuki K, Mizuno R, Oya M, et al.
  • Organizer: The107th American Urological Association Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2012-05-20
• [Book] Year Book of RCC2013 (2013)
  • Author(s): 水野隆一、大家基嗣
  • Total Pages: 207
  • Publisher: メディカルレビュー社