Song Mengjia, He Junyi, Pan Qiu-Zhong, Yang Jieying, Zhao Jingjing, Zhang Yao-Jun, Huang Yue, Tang Yan, Wang Qijing, He Jia, Gu Jiamei, Li Yongqiang, Chen Shiping, Zeng Jianxiong, Zhou Zi-Qi, Yang Chaopin, Han Yulong, Chen Hao, Xiang Tong, Weng De-Sheng, Xia Jian-Chuan
Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
Hepatology. 2021 May;73(5):1717-1735. doi: 10.1002/hep.31792.
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.
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.
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.
癌症相关成纤维细胞（CAFs）是导致肝癌发病的多细胞、基质依赖性改变的关键因素。然而，CAFs与肿瘤微环境（TME）中其他成分之间复杂的相互作用仍不清楚。本研究旨在探讨肝癌发病不同阶段CAFs、肿瘤细胞和肿瘤相关中性粒细胞（TANs）之间的细胞相互作用。
在肝癌-TME中，CAF衍生的心肌营养素样细胞因子1（CLCF1）增加了肿瘤细胞中趋化因子（C-X-C基序）配体6（CXCL6）和转化生长因子-β（TGF-β）的分泌，随后以自分泌方式促进肿瘤细胞干性，并以旁分泌方式促进TAN浸润和极化。此外，肝癌细胞分泌的CXCL6和TGF-β激活了CAFs的细胞外信号调节激酶（ERK）1/2信号通路，以产生更多的CLCF1，从而形成正反馈回路，加速肝癌进展。抑制ERK1/2或CLCF1/睫状神经营养因子受体信号通路在体外和体内均能有效削弱CLCF1介导的CAFs、肿瘤细胞和TANs之间的相互作用。在临床样本中，CLCF1-CXCL6/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。
本研究揭示了一种细胞因子介导的细胞相互作用和临床网络，涉及CLCF1-CXCL6/TGF-β轴，该轴调节CAFs、肿瘤干性和TANs之间的正反馈回路、肝癌进展和患者预后。这些结果可能支持CLCF1级联作为潜在的预后生物标志物，并表明选择性阻断CLCF1/睫状神经营养因子受体或ERK1/2信号通路可为肝癌患者提供有效的治疗靶点。
