Background
The tissue distribution of CAFs in the HCC microenvironment
Heterogeneous cellular origins of CAFs
Phenotypic characteristics of CAFs in HCC tissues
Phenotype | Protein markers | Function | Molecular mechanism | Reference | |
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Activated myofibroblast phenotype | α-SMA, collagen 1α, fibronectin | Maintain and enhance the stemness of HCC cells | In vitro: promote HCC cell proliferation, invasion, EMT In vivo: promote tumorigenesis, growth and metastasis | COMP | Sun et al. [41] |
α-SMA, vimentin | In vitro: promote proliferation, invasion | IL-6, IL-8, CCL2 | Mono et al. [42] | ||
α-SMA, FAP, vimentin | In vitro: increased sorafenib resistance, proliferation rate, migration, and invasion In vivo: promote tumorigenesis | HGF/c-Met/STAT3 IL-6/IL6R/STAT3 | Li et al. [43] | ||
α-SMA, FAP, vimentin | In vitro: promote proliferation, migration and invasion, and the expression of stemness genes In vivo: promote tumorigenesis and HCC growth | IL-6/STAT3/notch | Xiong et al. [44] | ||
α-SMA, PDGFR-α | Maintain and enhance the stemness of HCC cells | Notch 3 signaling | Liu et al. [45] | ||
α-SMA, FSP1, vimentin | In vivo: promote HCC initiation and growth | FOXQ1/NDRG1/CCL26 feedback loop | Luo et al. [46] | ||
α-SMA, FSP1, vimentin | In vitro: promote migration, invasion, EMT In vivo: promote metastasis | CCL2/CCL5/Hh, CCL7/CXCL16/TGF-β pathway | Liu et al. [47] | ||
Activated myofibroblast phenotype | α-SMA, FAP | Maintain and enhance the stemness of HCC cells | In vitro: promote proliferation, self-renewal In vivo: promote tumorigenesis | HGF/c-Met/Erk/FRA1/HEY1 signaling | Lau et al. [48] |
α-SMA, FAP, vimentin | In vitro: promote proliferation In vivo: promote growth | HGF | Jia et al. [49] | ||
α-SMA, vimentin | Enhance HCC blood supply | Promote vasculogenic mimicry | TGF-β, SDF-1 | Yang et al. [50] | |
α-SMA, FAP, vimentin | Immunosuppression | Recruit and promote the differentiation of neutrophils, monocytes, and dendritic cells into cells with immunosuppressive phenotypes | Recruitment: SDF-1α/CXCR4 Education: IL-6/STAT3 | ||
Mesenchymal stromal cell phenotype | Positive: CD90, CD73, CD105, CD29, CD44, CD166 Negative: CD34,CD31, CD45, HLA-DR | Immunosuppression | Attenuate the cytotoxic activity of NK cells (downregulation of granzyme B and perforin) | PEG2, IDO | Li et al. [54] |
Positive: CD90, CD44, CD29, CD13, CD105, CD166 Negative: CD34, CD45, CD117 multipotent differentiation: adipogenic, osteogenic, and pancreatic differentiation | – | – | – | Sukowati et al. [55] |
Biological functions of CAFs in HCC progression
The value of CAFs in predicting HCC prognosis
Selection criteria of HCC cases | Source/number/staining of HCC specimens | Quantification of immunohistochemistry | Mean DFS/OS | HCC prognosis | Predictive value | Reference | |||
---|---|---|---|---|---|---|---|---|---|
Methods | Cut-off value | High-density group | Low-density group | ||||||
HCC cases underwent curative radical surgery without neo-adjuvant radiotherapy or chemotherapy | Clinical cases/101 HCC patients/α-SMA | Stromal thickness was measured using the CRi Nuance multispectral imaging system | Mean value of stromal thickness: 238.6 μm | DFS: 3 months | DFS: 12 months | Inverse correlation with DFS | Independent prognostic factor for DFS | Fang et al. [25] | |
No modality other than LDLT available to treat patients with HCC and end-stage liver disease; no extrahepatic metastasis or macrovascular invasion such as portal vein or hepatic vein infiltration | Clinical cases/22 HCC patients/α-SMA | The percentage of α-SMA expression in the stromal area was calculated | α-SMA expression in stromal area: < 1%, < 10%, > 10% | > 10% | < 10% | > 1% | Inverse correlation with DFS and OS | Independent prognostic factor for DFS | Takamura et al. [23] |
– | – | – | |||||||
HCC without a history of preoperative treatment | Clinical cases/314 HCC patients/FAP | Scoring was performed according to staining intensity and the percentage of positive cells | Score (positive: 2, moderate staining in ≥5%, and 3, strong staining in ≥ 5% cells; negative: 0, staining in < 5% cells, and 1, weak staining in ≥5%) | – | – | No association with HCC prognosis | – | Kim et al. [24] |