Table 1.
The factors and pathways for CAF activation in the tumor/premalignant microenvironment.
| Cell origins | Factors | Signaling pathways and/or mechanism | Phenotypes and/or biomarkers | Reference |
|---|---|---|---|---|
| HSCs | SULF2 | TGF-β1/SMAD3 | α-SMA, FAP, and POSTN ↑ | (20) |
| TGF-β | TGF-β1/SMAD3 | α-SMA, FAP, and collagen ↑ | (21, 38, 39) | |
| CXCR4 | SDF-1/CXCR4/TGF-β | α-SMA, vimentin, FSP1, and FAP ↑ | (40) | |
| p300 | TGF-β1/SMAD2/3-TAZ and histone acetylation | CTGF, tenascin-C, POSTN, PDGF-C, and FGF2 ↑ | (26) | |
| IL-33 | IL-33/ST2 and MAPK | IL-6, TGF-β, α-SMA, and collagen ↑ | (41) | |
| PDGF-C | Desmin and αSMA ↑ | (29) | ||
| Exosomal miRNA-21 | PTEN/PDK1/AKT | α-SMA, VEGF, MMP2, MMP9, bFGF, and TGF-β ↑ | (28) | |
| CTHRC1 | TGF-β | α-SMA and migratory and contractile capacities ↑ | (32) | |
| BAFF | NF-κB | α-SMA and FAP ↑ | (42) | |
| STMN1 | MET | α-SMA, FSP, and HGF ↑ | (43) | |
| CTGF | α-SMA and IL-6 ↑ | (44) | ||
| p62/SQSTM1 | Vitamin D receptor binding | α-SMA, collagen, TGF-β, and PDGF ↓ | (24) | |
| Stromal fibroblasts | MCT4 | GLUT1 and lactate production ↑ | (45) | |
| Exosomal ITGB4 | ITGB4/BNIP3L | Lactate production ↑ | (46) | |
| CXCL6 and TGF-β | ERK1/2 | CLCF-1 ↑ | (21) | |
| NOX4 | Intracellular ROS generation and TGF-β | α-SMA and collagen 1 ↑ | (37, 47) | |
| TIMP-1 | MMP inhibition | α-SMA, FAP, and vimentin ↑ | (48) | |
| BMP4 | ACTA2, COL1A1, IL-6, IL-8, and CCL2 ↑ | (49) | ||
| ZEB1, CTGF | CCN2/CTGF | α-SMA and ZEB1 ↑ | (44, 50) | |
| Mesenchymal cells | Hypoxia | COX2 and PGE2 ↑ | (31) | |
| RvD1 | FPR2/ROS/FOXM1 | COMP and FOXM1 ↓ | (51) | |
| OPN | OPN–integrin interaction and MZF1-TGF-β1 | SMA, tenascin-C, vimentin, FSP-1, and MMPs↑ | (33, 52) | |
| Endothelial cells | Interstitial pressure and exosomal TGF-β | Endothelial to mesenchymal transition | α-SMA, FSP-1, and angiogenesis ↑ | (35) |
| HCC cells | TGF-β | EMT | α-SMA and FAP ↑ | (22, 36) |
HSC, hepatic stellate cell; SULF2, sulfatase 2; TGF-β: transforming growth factor-β; SMAD, Drosophila mothers against decapentaplegic protein; CXCL, C-X-C chemokine ligand; α-SMA, α-smooth muscle actin; FAP, fibroblast activation protein; POSTN, periostin; SDF-1, stromal cell-derived factor-1; FSP, ferroptosis suppressor protein; CTGF, connective tissue growth factor; FGF, fibroblast growth factor; IL, interleukin; MAPK, mitogen-activated protein kinase; PTEN, phosphatase and tensin homolog deleted on chromosome ten; PDK1, 3-phosphoinositide-dependent kinase-1; AKT, protein kinase B; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; GLUT, glucose transport-1; ITGB4, integrin-β4; ROS, reactive oxygen species; TIMP-1, tissue inhibitor of metalloproteinases; OPN, osteopontin; EMT, epithelial–mesenchymal transition. ↑：upregulation, ↓：downregulation.