2017年9月12日
Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90.
Scientific reports
- 巻
- 7
- 号
- 1
- 開始ページ
- 11292
- 終了ページ
- 11292
- 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.
- リンク情報
-
- DOI
- https://doi.org/10.1038/s41598-017-11848-z
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/28900199
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596021
- 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
- ID情報
-
- DOI : 10.1038/s41598-017-11848-z
- ISSN : 2045-2322
- PubMed ID : 28900199
- PubMed Central 記事ID : PMC5596021
- Web of Science ID : WOS:000410297900006