論文

査読有り
2017年9月

Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90

SCIENTIFIC REPORTS
  • Mariko Yoshida
  • ,
  • Taro Yamashita
  • ,
  • Hikari Okada
  • ,
  • Naoki Oishi
  • ,
  • Kouki Nio
  • ,
  • Takehiro Hayashi
  • ,
  • Yoshimoto Nomura
  • ,
  • Tomoyuki Hayashi
  • ,
  • Yoshiro Asahina
  • ,
  • Mika Ohwada
  • ,
  • Hajime Sunagozaka
  • ,
  • Hajime Takatori
  • ,
  • Federico Colombo
  • ,
  • Laura Porretti
  • ,
  • Masao Honda
  • ,
  • Shuichi Kaneko

7
1
開始ページ
11292
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41598-017-11848-z
出版者・発行元
NATURE PUBLISHING GROUP

Cancer stem cells (CSCs) are a pivotal target for eradicating hepatocellular carcinoma (HCC). We previously reported that distinctive CSCs regulating tumorigenicity (EpCAM(+) CSCs) and metastasis (CD90(+) CSCs) have different epithelial/mesenchymal gene expression signatures. Here, we examined the influence of sorafenib, a multiple-receptor tyrosine kinase inhibitor used as a first-line treatment for advanced HCC, on EpCAM(+) and CD90(+) CSCs. CD90(+) cells showed higher c-Kit gene/protein expression than EpCAM(+) cells. Sorafenib treatment reduced the number of CD90(+) cells with attenuated c-Kit phosphorylation, whereas it enriched the EpCAM(+) cell population. We evaluated the role of CD90(+) and EpCAM(+) CSCs in vivo by subcutaneously injecting these CSCs together in immune-deficient mice. We observed that sorafenib subtly affected the suppression of primary tumor growth maintained by EpCAM(+) CSCs, but completely inhibited the lung metastasis mediated by CD90(+) CSCs. We further evaluated the effect of sorafenib on extracellular vesicle (EV) production and found that sorafenib suppressed the production of EVs containing TGF-beta mRNA in CD90(+) cells and inhibited the cell-cell communication and motility of EpCAM(+) cells. Our data suggest the following novel effects of sorafenib: suppressing CD90(+) CSCs and inhibiting the production of EVs regulating distant metastasis.

Web of Science ® 被引用回数 : 11

リンク情報
DOI
https://doi.org/10.1038/s41598-017-11848-z
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28900199
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000410297900006&DestApp=WOS_CPL

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