Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90.
Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90.
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DOI：
10.1038/s41598-017-11848-z
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发表时间：
2017-09-12
影响因子：
4.6
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Yoshida M;Yamashita T;Okada H;Oishi N;Nio K;Hayashi T;Nomura Y;Hayashi T;Asahina Y;Ohwada M;Sunagozaka H;Takatori H;Colombo F;Porretti L;Honda M;Kaneko S
肿瘤干细胞（CSCs）是根治肝细胞癌（HCC）的关键靶点。我们先前报道了调节致瘤性（EpCAM+ CSC）和转移（CD 90 + CSC）的独特CSC具有不同的上皮/间充质基因表达特征。在这里，我们研究了索拉非尼（一种多受体酪氨酸激酶抑制剂，用作晚期HCC的一线治疗）对EpCAM+和CD 90 + CSC的影响。CD 90+细胞显示出比EpCAM+细胞更高的c-Kit基因/蛋白表达。索拉非尼治疗减少了CD 90+细胞的数量，减弱了c-Kit磷酸化，而它富集了EpCAM+细胞群。我们通过将这些CSC一起皮下注射到免疫缺陷小鼠中来评估CD 90+和EpCAM+ CSC在体内的作用。我们观察到索拉非尼微妙地影响EpCAM+ CSC维持的原发性肿瘤生长的抑制，但完全抑制CD 90 + CSC介导的肺转移。我们进一步评估了索拉非尼对细胞外囊泡（EV）产生的影响，发现索拉非尼抑制CD 90+细胞中含有TGF-β mRNA的EV的产生，并抑制EpCAM+细胞的细胞间通讯和运动。我们的数据表明索拉非尼具有以下新作用：抑制CD 90 + CSC和抑制调节远处转移的EV的产生。
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-β 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.
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DOI：
10.1002/hep.26168
发表时间：
2013-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Yamashita T;Honda M;Nakamoto Y;Baba M;Nio K;Hara Y;Zeng SS;Hayashi T;Kondo M;Takatori H;Yamashita T;Mizukoshi E;Ikeda H;Zen Y;Takamura H;Wang XW;Kaneko S
通讯作者：
Kaneko S
影响因子：
51.1
作者：
Faivre, Sandrine;Raymond, Eric;Cheng, Ann Lii
通讯作者：
Cheng, Ann Lii
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
3.7
作者：
Colombo F;Baldan F;Mazzucchelli S;Martin-Padura I;Marighetti P;Cattaneo A;Foglieni B;Spreafico M;Guerneri S;Baccarin M;Bertolini F;Rossi G;Mazzaferro V;Cadamuro M;Maggioni M;Agnelli L;Rebulla P;Prati D;Porretti L
通讯作者：
Porretti L
影响因子：
11.2
作者：
Liu, Li;Cao, Yichen;Carter, Christopher
通讯作者：
Carter, Christopher