Establishment of new target therapy depending on the origin of lung cancer stem cell

• Project/Area Number: 26461170
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kansai Medical University
• Principal Investigator: KUMANO Keiki 関西医科大学, 医学部, 准教授 (90396721)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺がん / 幹細胞 / 系譜追跡 / Bmi1

Outline of Final Research Achievements

Alveolar stem cells were tracked by lineage tacing system. Among stem cell markers, Bmi1 expressed in the some portion of alveolar type 2(AT2) cells (SPC(+) cells). After Radiation injury, both AT2 and AT1 cells were regenerated from Bmi1(+) cells.
Mutant form of Kras (Kras G12D) caused the clonal lung cancer development from one Bmi1(+) cells. On the other hand, all mice died after mutnat Kras was expressed in the SPC(+) alveolar type 2 cells within 8weeks. In this time point, the clonal expansion of SPC(+) cells were observed but no obvious lung cancer developed. This indicate that mice were dead due to the suffocation probably by the oversecretion of surfactant proteins. These results indicate lung cancer might be originated from the Bmi1(+) cells which are some part of AT2 cells.

Research Products

• [Journal Article] Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion. (2017)
  • Author(s): Hirotsugu Yanai, Naho Atsumi, Toshihiro Tanaka, Naohiro Nakamura, Yoshihiro Komai, Taichi Omachi, Kiyomichi Tanaka, Kazuhiko Ishigaki, Kazuho Saiga, Haruyuki Ohsugi, Yoko Tokuyama, Yuki Imahashi, Shuichi Ohe, Hiroko Hisha, Naoko Yoshida, Keiki Kumano, Masanori Kon and Ueno H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 41838-41847
  • DOI: 10.1038/srep41838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bmi1-positive cells in the lingual epithelium could serve as cancer stem cells in tongue cancer (2016)
  • Author(s): T Tanaka, N Atsumi, N Nakamura, H Yanai, Y Komai, T Omachi, K Tanaka, K Ishigaki, K Saiga, H Ohsugi, Y Tokuyama, Y Imahashi, H Hisha, N Yoshida, K Kumano, K Okazaki, and Ueno H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 39386-39391
  • DOI: 10.1038/srep39386
  • Peer Reviewed / Open Access
• [Journal Article] Maintenance of sweat glands by stem cells located in the acral epithelium. (2015)
  • Author(s): 1.Ohe S, Tanaka T, Yanai H, Komai Y, Omachi T, Kanno S, Tanaka K, Ishigaki K, Saiga K, Nakamura N, Ohsugi H, Tokuyama Y, Atsumi N, Hisha H, Yoshida N, Kumano K, Yamazaki F, Okamoto H, Ueno H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 466 Issue: 3 Pages: 333-338
  • DOI: 10.1016/j.bbrc.2015.09.022
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. (2015)
  • Author(s): 2.Iizuka H, Kagoya Y, Kataoka K, Yoshimi A, Miyauchi M, Taoka K, Kumano K, Yamamoto T, Hotta A, Arai S, Kurokawa M.
  • Journal Title: Exp Hematol. Volume: 43 Issue: 10 Pages: 849-857
  • DOI: 10.1016/j.exphem.2015.05.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intracellular signals of lung cancer cells as possible therapeutic targets. (2015)
  • Author(s): Tanaka K, Kumano K, Ueno H
  • Journal Title: Cancer Science Volume: 未定 Issue: 5 Pages: 489-496
  • DOI: 10.1111/cas.12643
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bmi1 expression in long-term germ stem cells. (2014)
  • Author(s): Komai Y, Tanaka T, Tokuyama Y, Yanai H, Ohe S, Omachi T, Atsumi N, Yoshida N, Kumano K, Hisha H, Matsuda T, Ueno H.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 6175-6186
  • DOI: 10.1038/srep06175
  • Peer Reviewed
• [Journal Article] Generation of induced pluripotent stem cells derived from primary and secondary myelofibrosis patient samples (2014)
  • Author(s): Hosoi M, Kumano K, Taoka K, Arai S, Kataoka K, Ueda K, Kamikubo Y, Takayama N, Otsu M, Eto K, Nakauchi H, Kurokawa M
  • Journal Title: Exp Hematol Volume: (in press) Issue: 9 Pages: 816-25
  • DOI: 10.1016/j.exphem.2014.03.010
  • Peer Reviewed / Open Access
• [Journal Article] The IL-2/CD25 Axis Maintains Distinct Subsets of Chronic M yeloid Leukemia-initiating Cells. (2014)
  • Author(s): Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T.
  • Journal Title: Blood Volume: 123 Issue: 16 Pages: 2540-2549
  • DOI: 10.1182/blood-2013-07-517847
  • Peer Reviewed / Open Access
• [Journal Article] Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. (2014)
  • Author(s): Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 2 Pages: 528-542
  • DOI: 10.1172/jci68101
  • Peer Reviewed