Table 1.
Summary of tumor stromal actions in the TME of CCA
| Cells | The research direction | Result | Reference | Reference number |
|---|---|---|---|---|
| CAF | The immune mechanism | Hepatic stellate cell-derived CAFs are the main tumor-interacting population in ICC. | Affo et al. (2021) | 17 |
| CAF | The immune mechanism | Tumor exosomal miR-9-5p elicited IL-6 expression in vCAFs,thereby leading to epigenetic alterations in ICC. | Zhang et al. (2020) | 18 |
| CAF | Prognostic marker | Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through FOXP3+ TILs regulation. CAV1 expression in CAFs can be a therapeutic target for ICC. | Lan et al. (2021) | 124 |
| CAF | The immune mechanism | PDGF-D stimulates VEGF-C and VEGF-A production by fibroblasts, resulting in expansion of the lymphatic vasculature and tumor cell intravasation. | Cadamuro et al. (2019) | 20 |
| CAF | Prognostic marker | The ICC patients with immature CAF phenotype had a more aggressive feature and significantly poorer OS than those with mature phenotype. | Zhang et al. (2017) | 125 |
| CAF | The immune mechanism | Downregulation of tumor‐derived exosomal miR-34c induces cancer‐associated fibroblast activation to promote CCA progress. | Qin et al. (2021) | 19 |
| CAF | The immune mechanism | FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the TME via STAT3-CCL2 Signaling. | Yang et al. (2016) | 21 |
| CAF | The immune mechanism | CAFs promoted proliferation, mi-gration, and invasion of CCA cells in vitro and boosted tumor growth in vivo. Furthermore, it was demonstrated that stroma enriched with α- SMA- positive CAFs was associated with poor prognosis of patients with ICC. | Sha et al. (2018) | 126 |
| CAF | Immunotherapy | The potential of repeated CAF-targeted PTT for the treatment of desmoplastic CCA after intra-tumoral administration. | Nicolás-Boluda et al. (2020) | 127 |
| CAF | The immune mechanism | IL-6 Secreted by CAFs Inhibits Autophagy and Reduces the Chemosensitivity of CCA Cells. | Thongchot et al. (2021) | 128 |
| CAF | The immune mechanism | ZEB1 plays a key role in CCA progression by regulating tumor cell-CAF crosstalk, leading to tumor dedifferentiation and CAF activation. | Lobe et al. (2021) | 129 |
| CAF | Prognostic marker | FAP overexpression is evident in dCCA. There was a positive association between epithelial FAP expression and better survival. | Byrling et al. (2020) | 130 |
| CAF | The immune mechanism | Treatment with LTB4 that were elevated in CAF-educated MDSCs or blockade of BLT2 that was preferentially expressed in stem-like ICC cells significantly reduced stemness-enhancing effects of CAF-educated MDSCs. | Lin et al. (2022) | 131 |
| CAF | The immune mechanism | To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch. | Vaquero et al. (2018) | 132 |
| CAF | immunotherapy | PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice- bearing aggressive ICC. | Aoki et al. (2021) | 133 |
| CAF | Immunotherapy | Conditioned culture medium from CCA-derived CAFs further stimulated IL-6 secretion in CCA cells and promoted the migration of invasive cholangiocytes, while the nutrient resveratrol strongly counteracted this effect. | Thongchot et al. (2018) | 134 |
| CAF | Prognostic marker | High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in CCA. | Yangngam et al. (2020) | 22 |
| CAF | The immune mechanism | Fibroblast growth factor receptor inhibition induces loss of matrix MCL1 and necrosis in CCA. | Kabashima et al. (2018) | 135 |
| CAF | The immune mechanism | CCA Cells Secreting PDGF-D Strongly Stimulate Fibroblast Recruitment, an Effect That Is Significantly Reduced by PDGFRb Antagonism and by PDGF-D siRNA. |
Cadamuro et al. (2013) | 136 |
| CAF | Immunotherapy | MiR-206 suppresses the deterioration of intrahepatic CCA and promotes sensitivity to chemo-therapy by inhibiting interactions with stromal CAFs. |
Yang et al. (2022) | 24 |
| CAF | The immune mechanism | The microRNA-15a-PAI-2 axis in CCA-associated fibroblasts promotes migration of cancer cells. | Utaijaratrasmi et al. (2018) | 137 |
| CAF | Immunotherapy | Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. | Yamanaka et al. (2020) | 23 |
| CAF | Immunotherapy | Navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. | Mertens et al. (2013) | 138 |
| Endothelial cell | immunotherapy | Anti-Glypican-1 Antibody-drug Conjugate targets CCA cells and GPC1 in vascular endothelial cells, and directly or indirectly inhibits CCA growth by inhibiting tumor angiogenesis. | Yokota et al. (2021) | 37 |
| Endothelial cell | Prognostic marker | CD105 is a tumor-associated endothelial cell marker. High expression of CD105 was independently associated with poor survival in patients with CCA. | Nair et al. (2020) | 38 |
| Endothelial cell | The immune mechanism | Plasmalemma vesicle-associated protein (PLVAP) is associated with angiogenesis in CCA. DKK1 secreted by CCA cells promotes tumor angiogenesis through the DKK1/CKAP4/PI3K/PLVAP pathway. | Wang et al. (2021) | 28 |
| Endothelial cell | The immune mechanism | ERK5 is highly expressed in human CCA cells, regulates the content of VEGF and angiopoietin 1 in the tumor microenvironment, and induces angiogenesis in tumor-associated endothelial cells. | Gentilini et al. (2021) | 30 |
| Endothelial cell | The immune mechanism | Circ-CCAC1 of CCA-derived EVs was transferred into CCA vascular endothelial monolayer cells, disrupting endothelial barrier integrity and inducing angiogenesis. | Xu et al. (2021) | 31 |
| Endothelial cell | The immune mechanism | Pcca cell-derived HMGB1 upregulates VEGFR2 expression in vascular endothelial cells and induces ectopic angiogenesis by in vitro and in vivo experiments. | Xu et al. (2019) | 29 |
| Endothelial cell | The immune mechanism | The secretion of PDGF-D by CCA cells resulted in increased levels of VEGF-C and VEGF-A secreted by fibroblasts and increased endothelial cell permeability. | Cadamuro et al. (2019) | 20 |
| Endothelial cell | The immune mechanism | TCF21 was decreased in CCA tissues or cell lines compared to normal tissues. TCF21 exerts anti-angiogenic activity through PI3K/Akt and ERK1/2 signaling pathways. | Duan et al. (2019) | 36 |
| Endothelial cell | The immune mechanism | THBS1, THBS2 and PEDF are up-regulated in the ICC microenvironment. The ability of THBS1, THBS2 and PEDF to inhibit endothelial cell angiogenesis was demonstrated by in vivo experiments. | Carpino et al. (2021) | 139 |
| Endothelial cell | The immune mechanism | eNOS is upregulated in CCA tissues and their cell lines, promoting angiogenesis and metastasis in CCA. | Suksawat et al. (2017) | 26 |