Analysis of the tumor microenvironment promoting the cancer stem cells

• Project/Area Number: 15K08408
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kyorin University
• Principal Investigator: Chiba Tomohiro 杏林大学, 医学部, 講師 (60398617)
• Research Collaborator: Kamma Hiroshi ; Sumiishi Ayumi ; Sasamoto Kaoruko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: cancer stem cell / tumor microenvironment / glioblastoma / Stat3 / p53 / 癌幹細胞 / ニッチ / グリオブラストーマ / 微小環境 / STAT3 / STAT5

Outline of Final Research Achievements

In the current study, we analyzed the microenvironment promoting cancer stem cells (CSC). Previous data have shown that CSC can be induced from cancer cells through epigenetic regulation induced by Stat3 and p53.
To test if CSC niche is induced by cellular stress such as chemotherapy and hypoxia, we carried out detailed analysis of the GBM-CSC induction. As a result, we revealed that GBM-CSC is induced by anti-cancer drugs, hypoxia and acidic buffer via activation of Stat3 and Stat 5. These data provide a novel insight into chemotherapy of GBM.

Academic Significance and Societal Importance of the Research Achievements

GBMの標準治療は、放射線療法とtemozolomide（TMZ）の併用療法（Stuppレジメン）である。しかしながら、GBMを治療により根治することは未だ困難である。特に再発は大きな問題となっており、癌幹細胞が再発の大きな要因になっていると推定されている。本研究で得られた細胞ストレスによってStat3/Stat5の活性化が起こり、癌幹細胞を誘導する微小環境がもたらされるという知見は今後の治療薬開発に寄与するものと考える。

Research Products

• [Journal Article] Clinical Pathology in The Future: do Genetic Analyses Replace The Morphological Observation? (2016)
  • Author(s): Tomohiro Chiba
  • Journal Title: EC Cancer (E-Cronicon) Volume: 2 Pages: 26-27
  • Open Access
• [Journal Article] STAT3 Inhibitors for Cancer Therapy -the Rationale and Remained Problems (2016)
  • Author(s): Tomohiro Chiba
  • Journal Title: EC Cancer (E-Cronicon) Volume: 1(S1)
  • Peer Reviewed / Open Access
• [Journal Article] PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells. (2016)
  • Author(s): Ishii J, Yazawa T, Chiba T, Shishido-Hara Y, Arimasu Y, Sato H, Kamma H.
  • Journal Title: Endocrinology Volume: 157 Issue: 3 Pages: 1289-1298
  • DOI: 10.1210/en.2015-1973
  • Peer Reviewed
• [Journal Article] Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes. (2015)
  • Author(s): Yang CM, Chiba T, Brill B, Delis N, von Manstein V, Vafaizadeh V, Oellerich T, Groner B
  • Journal Title: International Journal of Cancer Volume: 印刷中 Issue: 10 Pages: 2296-2309
  • DOI: 10.1002/ijc.29606
  • Peer Reviewed
• [Presentation] 右側頭葉悪性末梢神経鞘腫瘍の一例 (2017)
  • Author(s): 千葉知宏、山田健、島田大輔、齊藤邦昭、小林啓一、藤原正親、永根基雄、柴原純二
  • Organizer: 日本脳腫瘍病理学会
• [Presentation] Challenges in WHO2016 update-based diagnosis and treatment of anaplastic gliomas (2017)
  • Author(s): Motoo Nagane, Keiichi Kobayashi, Kuniaki Saito, Saki Shimizu, Kaori Suzuki, Tomohiro Chiba, Junji Shibahara, Yoshiaki Shiokawa
  • Organizer: Asian Society for Neuro-Oncology 2017 (ASNO17)
  • Int'l Joint Research