间质细胞
旁分泌信号
癌症研究
自分泌信号
细胞因子
串扰
癌症
肿瘤微环境
生物
肿瘤进展
免疫学
受体
光学
物理
生物化学
遗传学
肿瘤细胞
作者
Mengjia Song,Junyi He,Qiuzhong Pan,Jieying Yang,Jing Wang,Yaojun Zhang,Yue Huang,Yan Tang,Li Wang,Jia He,Jiamei Gu,Yongqiang Li,Shiping Chen,Jianxiong Zeng,Ziqi Zhou,Chih-Ping Yang,Yulong Han,Hao Chen,Tong Xiang,Desheng Weng,Jian‐Chuan Xia
出处
期刊:Hepatology
[Wiley]
日期:2021-04-29
卷期号:73 (5): 1717-1735
被引量:175
摘要
Background and Aims Cancer‐associated fibroblasts (CAFs) are key players in multicellular, stromal‐dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor‐associated neutrophils (TANs) during different stages of HCC pathogenesis. Approach and Results In the HCC‐TME, CAF‐derived cardiotrophin‐like cytokine factor 1 (CLCF1) increased chemokine (C‐X‐C motif) ligand 6 (CXCL6) and TGF‐β secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF‐β secreted by HCC cells activated extracellular signal‐regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1‐mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo . In clinical samples, up‐regulation of the CLCF1−CXCL6/TGF‐β axis exhibited a marked correlation with increased cancer stem cells, “N2”‐polarized TANs, tumor stage, and poor prognosis. Conclusions This study reveals a cytokine‐mediated cellular crosstalk and clinical network involving the CLCF1−CXCL6/TGF‐β axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.
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