Cancer stem cell characteristics in mTOR inhibitor-resistant kidney cancer cells

• Project/Area Number: 17K11121
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Akita University
• Principal Investigator: Numakura Kazuyuki 秋田大学, 医学部附属病院, 講師 (90566415)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腎細胞癌 / 癌幹細胞 / mTOR阻害薬 / Aldehyde dehydrogenase / 脂肪由来幹細胞 / PI-3K / 泌尿器科 / mTOR

Outline of Final Research Achievements

Aldehyde dehydrogenase (ALDH) activity increased in a time-dependent manner, showing resistance to EVE but not 786-O PAR. Cancer stem cell characteristics were confirmed by tumor sphere-formation assay (45.8 versus 6.3, p < 0.001) and colony formation assay, which showed tolerance to irradiation (RTx) (area % of colony at 4-Gy RTx: 3.02% versus 0.55%, p = 0.01), and supported by an increase in G0/G1 phase (53.4% versus 42.0% p = 0.04) via bromodeoxyuridine assay. ALDH activity by flow cytometry showed marked increasing ALDH-positive sub-populations (28.1% versus 0.3%, p < 0.001), and inhibition of ALDH activity by disulfiram (ALDH-specific inhibitor) showed a significant decrease in cell viability .

Academic Significance and Societal Importance of the Research Achievements

mTORi耐性RCCにおいて癌幹細胞特性が有意に亢進していることが明らかになった。ALDHは癌幹細胞の維持する上で重要な役割を果たしており、mTORi耐性克服の標的となる可能性がある

Research Products

• [Journal Article] First-line axitinib therapy is less effective in metastatic renal cell carcinoma with spindle histology (2020)
  • Author(s): Numakura Kazuyuki、Kobayashi Mizuki、Muto Yumina、Sekine Yuya、Takahashi Makoto、Kashima Soki、Yamamoto Ryohei、Koizumi Atsushi、Nara Taketoshi、Saito Mitsuru、Narita Shintaro、Nanjyo Hiroshi、Habuchi Tomonori
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 20089-20089
  • DOI: 10.1038/s41598-020-77135-6
  • Peer Reviewed / Open Access
• [Journal Article] Robotic-assisted laparoscopic partial nephrectomy for renal cell carcinoma in horseshoe kidney: a hybrid technique with conventional laparoscopic surgery (2020)
  • Author(s): Numakura Kazuyuki、Muto Yumina、Yamamoto Ryohei、Koizumi Atsushi、Nara Taketoshi、Kanda Sohei、Saito Mitsuru、Narita Shintaro、Inoue Takamitsu、Habuchi Tomonori
  • Journal Title: International Cancer Conference Journal Volume: 9 Issue: 4 Pages: 199-202
  • DOI: 10.1007/s13691-020-00420-8
  • Peer Reviewed
• [Journal Article] Efficacy and safety of nivolumab for renal cell carcinoma in patients over 75?years old from multiple Japanese institutes (2020)
  • Author(s): Numakura Kazuyuki、Kobayashi Mizuki、Hatakeyama Shingo、Naito Sei、Horikawa Yohei、Tanaka Toshikazu、Kamada Sachiko、Muto Yumina、Yamamoto Ryohei、Koizumi Atsushi、Nara Taketoshi、Kanda Sohei、Saito Mitsuru、Narita Shintaro、Inoue Takamitsu、Shimoda Naotake、Tsuchiya Norihiko、Ohyama Chikara、Habuchi Tomonori
  • Journal Title: International Journal of Clinical Oncology Volume: 25 Issue: 8 Pages: 1543-1550
  • DOI: 10.1007/s10147-020-01693-y
  • Peer Reviewed / Open Access
• [Journal Article] Robot-assisted laparoscopic pyeloplasty for ureteropelvic junction obstruction with duplex system. (2020)
  • Author(s): Numakura K, Muto Y, Saito M, Narita S, Inoue T, Habuchi T.
  • Journal Title: Urol Case Rep Volume: 30 Pages: 101138-101138
  • DOI: 10.1016/j.eucr.2020.101138
  • Peer Reviewed / Open Access
• [Journal Article] Overweight Patients Less Improved Kidney Function After Laparoscopic Surgery for Adrenocortical Adenoma With Excess Cortisol Secretion. (2019)
  • Author(s): Numakura K, Nara T, Kanda S, Saito M, Narita S, Inoue T, Habuchi T.
  • Journal Title: Front Endocrinol (Lausanne). Volume: 10 Pages: 572-572
  • DOI: 10.3389/fendo.2019.00572
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of anti-PD-1 antibody nivolumab in Japanese patients with metastatic renal cell carcinoma: A retrospective multicenter analysis. (2019)
  • Author(s): Numakura K, Horikawa Y, Kamada S, Koizumi A, Nara T, Chiba S, Kanda S, Saito M, Narita S, Inoue T, Shimoda N, Habuchi T.
  • Journal Title: Mol Clin Oncol. Volume: 11 Pages: 320-324
  • DOI: 10.3892/mco.2019.1887
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients (2018)
  • Author(s): Numakura Kazuyuki、Fujiyama Nobuhiro、Takahashi Makoto、Igarashi Ryoma、Tsuruta Hiroshi、Maeno Atsushi、Huang Mingguo、Saito Mitsuru、Narita Shintaro、Inoue Takamitsu、Satoh Shigeru、Tsuchiya Norihiko、Niioka Takenori、Miura Masatomo、Habuchi Tomonori
  • Journal Title: Oncotarget Volume: 9 Issue: 38 Pages: 25277-25284
  • DOI: 10.18632/oncotarget.25423
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients (2018)
  • Author(s): Kazuyuki Numakura, Nobuhiro Fujiyama, Makoto Takahashi, Ryoma Igarashi, Hiroshi Tsuruta, Atsushi Maeno, Mingguo Huang, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Shigeru Satoh, Norihiko Tsuchiya, Takenori Niioka, Masatomo Miura and Tomonori Habuchi
  • Journal Title: Oncotarget Volume: -
  • Peer Reviewed / Open Access
• [Presentation] Panel discussion on renal cell cancer: How do you treat this patient? (2019)
  • Author(s): Numakura ,K
  • Organizer: The 34th Annual European Association of Urology Congress, March, Barcelona, Spain
  • Int'l Joint Research
• [Presentation] Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients (2019)
  • Author(s): Numakura, K., Fujiyama, N., Takahashi, M., Igarashi, R., Nara, T., Chiba, S., Kanda, S., Saito, M., Narita, S., Inoue, T., Habuchi, T
  • Organizer: The 34th Annual European Association of Urology Congress, March, Barcelona, Spain
  • Int'l Joint Research
• [Presentation] Influence of genetic polymorphisms of vascular endothelial related genes on clinical outcome of axitinib in patients with metastatic renal cell carcinoma (2019)
  • Author(s): Numakura, K., Igarashi, R., Takahashi, M., Nara, T., Chiba, S., Kanda, S., Saito, M., Narita, S., Inoue, T., Habuchi, T.
  • Organizer: The 34th Annual European Association of Urology Congress, March, Barcelona, Spain
  • Int'l Joint Research
• [Presentation] CLINICAL IMPLICATIONS OF SUNITINIB AND N-DESETHYL-SUNITINIB PLASMA CONCENTRATIONS FOR TREATMENT OUTCOME IN METASTATIC RENAL CELL CARCINOMA PATIENTS. (2019)
  • Author(s): Numakura, K., Fujiyama, N., Takahashi, M., Tsuruta, H., Maeno, A., Saito, M., Inoue, T., Narita, S., Huang, M., Satoh, S., Niioka, T., Miura, M., Habuchi, T.
  • Organizer: 34th Annual EAU Congress in Barcelona, 15 - 20 March 2019.
  • Int'l Joint Research
• [Presentation] Cancer stem cell feature can induce resistance to mTOR inhibitors via the Notch pathway in renal cell carcinomas. (2018)
  • Author(s): Numakura, K., Novac, J., Pignon, J. C., Choueiri, T., Sabina, S.
  • Organizer: The 113th Annual Meeting of the American Urological Association, May, San Francisco, CA, USA
  • Int'l Joint Research