Table 1.

Impact of CAFs on HCC progression.

Authors	Type of Trial	Signaling Pathways, Mediators and Key Findings	Reference
Mazzocca et al., 2011	Clinical/Experimental	HCC cells secrete lysophostatidic acid (LPA), which promotes transdifferentiation of peritumoral tissue fibroblasts (PTFs) into CAFs HCC-secreted LPA accelerates HCC progression through recruitment of PTFs and promotion of their differentiation into myofibroblasts Higher serum levels of LPA are associated with worse survival	[70]
Lau et al., 2016	Clinical/Experimental	The presence of α-SMA+ CAFs correlates with poor clinical outcomes CAF-derived HGF regulates liver tumor-initiating cells (T-ICs) through activation of FRA1 in an ERK1/2-dependent manner HGF-induced FRA1 activation was associated with fibrosis-dependent development of HCC in a STAM NASH-HCC mouse model	[30]
Rhee et al., 2018	Experimental	Keratin 19 (KRT19) expression in HCC is regulated via crosstalk between CAFs and HCC cells through a MET-ERK1/2-AP1 and SP1 pathway HSCs upregulate transcription and translation of KRT19 in HCC cells via paracrine interactions HSC-derived HGF activates c-MET and the MEK-ERK1/2 pathway, which upregulates KRT19 expression in HCC cells In HCC specimens, HGF and KRT19 protein expression correlated with CAF levels	[72]
Zhang et al., 2017	Experimental	A significant reduction in the miR-320a level in CAF-derived exosomes Stromal cells could transfer miR-329a to HCC cells The miR-320a-PBX3 pathway inhibits HCC progression through suppression of activation of the MAPK pathway CAF-mediated HCC progression is partially related to loss of antitumor miR-320a in the exosomes of CAFs	[74]
Affo et al., 2017	Clinical/Experimental	CAFs play a key role in development and progression of HCC	[76]
Xu et al., 2022	Clinical/Experimental	CAF-derived chemokine CCL5 enhances HCC metastasis through triggering of the HIF1α/ZEB1 pathway HCC-derived CAFs promote migration and invasion of HCC cells and boosted metastasis to the lungs of NOD/SCID mice CAF-derived CCL5 inhibits ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) under normoxia, thereby upregulating the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and inducing epithelial mesenchymal transition (EMT)	[16]
Yang et al., 2020	Experimental	Endosialin is mainly expressed in CAFs in HCC, and its expression inversely correlates with patient prognosis Endosialin interacts with CD68 to recruit macrophages and regulates expression of GAS6 in CAFs to mediate M2 polarization of macrophages Endosialin-positive CAFs promote HCC progression	[82]
Cheng et al., 2018	Experimental	HCC-CAFs induce chemotaxis of PDL1+ neutrophils through the IL6-STAT3 pathway that boosts immune suppression in HCC	[83]
Song et al., 2021	Clinical/Experimental	CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increases chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-β secretion in HCC cells, which promotes HCC-cell stemness and TAN infiltration and polarization HCC-derived CXCL6 and TGF-β activate ERK1/2 signaling of CAFs to produce more CXCF1 and promote HCC progression Selective blocking of CLCF1 or ERK1/2 signaling could provide an effective therapeutic target for HCC patients	[69]
Qi et al., 2022	Experimental	CAF-derived exosomal miR-20-a-5p promotes HCC progression through the LIMA1-mediated Wnt/β-catenin signaling pathway LIMA1 is downregulated via CAF-derived exosomes that carry oncogenic miR-20a-5p in HCC	[63]