骨肉腫幹(OSi)細胞において, 間葉系幹細胞の性質を有するAO細胞は抗癌剤(アドリアマイシン及びシスプラチン)に対して高い抵抗性を示した。抗癌剤耐性のAO細胞にROCK阻害薬のFasudilを単剤投与すると, アクチン細胞骨格の動態変化を介して転写調節因子のMKL1の核移行及び転写が抑制され, 脂肪細胞への終末分化が誘導された。またFasudilはin vitro及びin vivoでのAO細胞の腫瘍形成性を抑制した。以上の結果から, 抗癌剤耐性のAO細胞のアクチン細胞骨格の動態を制御することで, 脂肪分化転換を誘導し腫瘍抑制できることが明らかとなった。
Osteosarcoma-initiating (OSi) cells are composed of two distinct types : AO cells, which have characteristics similar to mesenchymal stem cells, and AX cells, which have those similar to osteo-chondro progenitor cell and highly tumorigenic. We found that AO cells are highly resistant to chemotherapeutic agents, such as adriamycin and cisplatin. Treatment with the ROCK inhibitor fasudil alone induced remodeling of the actin cytoskeleton and inactivation of the transcriptional coactivator MKL1, resulting in the terminal adipocyte differentiation of chemoresistant stem-like AO cells. Furthermore, fasudil significantly suppressed in vitro growth and in vivo tumorigenesis of AO cells. Our findings suggest that induction of trans-differentiation by regulating actin cytoskeleton dynamics is a potential approach for chemoresistant stem-like OS cells.

研究種目 : 若手研究(B)
研究期間 : 2016～2017
課題番号 : 16K18426
研究分野 : 腫瘍生物学