Multi-step regulation mechanism of hypoxia-induced cancer stem cell of glioblastoma: relationship with tumor-stroma interaction

Research Project

Project/Area Number	17K15653
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Human pathology
Research Institution	Kitasato University
Principal Investigator	Inukai Madoca 北里大学, 医学部, 助教 (10525695)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	膠芽腫 / グリオーマ幹細胞 / S100A4 / Myosin9 / 低酸素 / がん幹細胞 / S100 A4 / Sox9 / 癌幹細胞
Outline of Final Research Achievements	The role of the S100A4 / Myosin9 (MYH9) system in glioblastoma stem cell transformation was investigated. As a result, a large number of S100A4 / MYH9-positive glioblastoma cells were found in the hypoxic region around the necrotic site in the glioblastoma tissue. At the same time, Nestin expression of a stem cell marker was enhanced. (2) S100A4 / MYH9 binding frequently occurred in the cytoplasm of glioblastoma cells in the hypoxic region by the in situ PLA method. (3) S100A4 / SM-actin-positive tumor cells were observed around the small blood vessel and in contact with the blood vessel wall. ④ Under simulated hypoxia caused by cobalt chloride, glioblastoma cultured cells KS-1 showed increased expression of S100A4 and MYH9. From the above, S100A4-positive glioblastoma cells have a possibility of contributing to glioblastoma stem cell transformation through association with S100A4 / MYH9 in a hypoxic niche or a vascular niche.
Academic Significance and Societal Importance of the Research Achievements	我が国で年間2千人の患者が発生する膠芽腫は、5年生存率が10％前後と極めて予後不良で、その原因の一つに自己複製能・多分化能を特徴とするグリオーマ幹細胞の存在がある。膠芽腫の新規治療戦略として、癌幹細胞の“幹”細胞としての形質 “stemness”を失わせることができれば、その高い腫瘍原性能（癌細胞集団を供給し再発巣を作る力）を喪失させ全腫瘍細胞集団を死滅させることが可能になる。本研究では、S100A4/MYH9 axisが低酸素・血管ニッチでの幹細胞化機構に密接に関与する可能性を得た。今後、この成果をさらに発展させることで膠芽腫の新規治療法の確立を目指す基礎研究に発展する可能性がある。