慢性肝炎与肝癌干细胞:冰冻三尺非一日之寒
  • 二乙基亚硝胺处理制备大鼠肝硬化模型,肝硬化大鼠分离出的肝前体细胞(LPC)移植到NOD/SCID小鼠,皮下生成肝癌,提示LPC向肝癌干细胞(LCSC)的恶性转化;
  • 体内清除枯否细胞可减轻转化LPC的LCSC性能,抑制CK19(+)OV6(+)肿瘤的发生,LPC与巨噬细胞共同培养,LCSC性能增强;
  • 巨噬细胞分泌的TNF-α通过下调泛素D和检查点激酶2而驱动LPC的染色体不稳定,通过TNFR1/Src/STAT3通路增强LPC自我更新能力,协同促进LPC向LCSC的转化。
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Hepatology [IF:17.425]

Chronic Inflammation-elicited Liver Progenitor Cell Conversion to Liver Cancer Stem Cell with Clinical Significance

慢性炎症引出的肝前体细胞转换为具有临床意义的肝癌干细胞

10.1002/hep.29372

2017-07-17, Article

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The substantial heterogeneity and hierarchical organization in liver cancer supports the theory of liver cancer stem cell (LCSC). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in NOD/SCID mice, suggesting the malignant transformation of LPC toward LCSC. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed CK19(+) OV6(+) tumor occurrence. Conversely, LPCs co-cultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted TNF-α triggered chromosomal instability in LPCs via the deregulation of ubiquitin D and Checkpoint kinase 2, and enhanced the self-renewal of LPCs through TNFR1/Src/STAT3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that CK19(+) OV6(+) liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. In conclusion, our results not only clarified the cellular and molecular mechanism underlying the inflammation-mediated LCSC generation, but also provided a novel molecular classification for the individualized treatment of liver cancer. This article is protected by copyright. All rights reserved.

First Authors:
Xiao-Feng Li,Cheng Chen,Dai-Min Xiang,Le Qu

Correspondence Authors:
Hong-Yang Wang,Jin Ding

All Authors:
Xiao-Feng Li,Cheng Chen,Dai-Min Xiang,Le Qu,Wen Sun,Xin-Yuan Lu,Teng-Fei Zhou,Shu-Zhen Chen,Bei-Fang Ning,Zhuo Cheng,Ming-Yang Xia,Wei-Feng Shen,Wen Yang,Wen Wen,Terence Kin Wah Lee,Wen-Ming Cong,Hong-Yang Wang,Jin Ding

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