Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression

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.

Automated summary

This study revealed 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. The up-regulation of the CLCF1-CXCL6/TGF-beta axis in clinical samples showed a correlation with increased cancer stem cells, N2-polarized TANs, tumor stage, and poor prognosis. This suggests the CLCF1 cascade could be a potential prognostic biomarker and targeting CLCF1/ ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.