Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression
Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression
复制标题
癌症相关的成纤维细胞介导的细胞串扰支持肝细胞癌的进展。
DOI：
10.1002/hep.31792
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发表时间：
2021-05-01
期刊：
影响因子：
13.5
通讯作者：
Xia, Jian-Chuan
中科院分区：
文献类型：
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作者：
Song, Mengjia;He, Junyi;Xia, Jian-Chuan
背景和目的癌相关成纤维细胞（CAF）是多细胞、基质依赖性改变导致HCC发病机制的关键参与者。然而，CAF和肿瘤微环境（TME）中其他组分之间的复杂串扰仍不清楚。本研究旨在探讨肝癌发病过程中不同阶段CAF、肿瘤细胞和肿瘤相关中性粒细胞（TANs）之间的细胞串扰。方法和结果在肝癌TME中，CAF衍生的心肌营养素样细胞因子1（CLCF 1）增加趋化因子表达。（C-X-C基序）配体6（CXCL 6）和肿瘤细胞中的TGF-β分泌，其随后以自分泌方式促进肿瘤细胞的干细胞性，并以旁分泌方式促进TAN浸润和极化。此外，HCC细胞分泌的CXCL 6和TGF-β激活CAFs的细胞外信号调节激酶（ERK）1/2信号，产生更多的CLCF 1，从而形成正反馈回路，加速HCC进展。抑制ERK 1/2或CLCF 1/睫状神经营养因子受体信号传导在体外和体内均有效地损害了CAF、肿瘤细胞和TAN之间的CLCF 1介导的串扰。在临床样本中，CLCF 1-CXCL 6/TGF-β轴的上调与癌症干细胞增加、“N2”极化TANs、肿瘤分期和不良预后显著相关。结论这项研究揭示了一个涉及CLCF 1-CXCL 6/TGF-β轴的马槟榔碱介导的细胞串扰和临床网络，该网络调节CAFs、肿瘤干性和TANs之间的正反馈回路，HCC进展，和患者预后。这些结果可能支持CLCF 1级联作为一个潜在的预后生物标志物，并表明选择性阻断CLCF 1/睫状神经营养因子受体或ERK 1/2信号转导可以为HCC患者提供一个有效的治疗靶点。
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-beta 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-beta 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-beta 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-beta 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.