Table 1.
The effect of EV components in TME and CCA progression.
| Source/EVs Cargoes | Effect in TME | Role in CCA | Expression Levels |
|---|---|---|---|
| CCA cells | |||
| MiR-34c [68] | CAF activation, tumor development | Tumor promoter | Upregulated |
| MiR-30e [69] | EMT suppression/targeting Snail/ Suppression of tumor invasion/metastatic dissemination |
Tumor suppressor | Downregulated |
| miR-195 [70] | Limitation of tumor growth/progression (cell culture model) | Tumor suppressor | Downregulated |
| MiR-200b-3p MiR-200c-3p [71] |
↑ tumor stage, growth, diagnostic biomarker | Tumor promoter Tumor promoter |
Upregulated Upregulated |
| miR-183-5p [72,73] |
iCCA progression via PD-L1 overexpression in macrophages aiming at HPGD in mast cells and CCA cells ↑ (PGE2) and PTGER1 stimulation ↑ VEGF release by mast cells, promoting neoangiogenesis |
Tumor promoter | Upregulated |
| Circ-0000284 [75] | Cholangiocyte malignant transformation miR-637/LY6E pathway |
Tumor promoter | Upregulated |
| Circ-CCAC1 [76] | Interacting with endothelial cells/ Promotion of neoangiogenesis Tumor growth/migration Sponging the miR-514a-5p/↑ YY1, ↑ CAMLG |
Tumor promoter | Upregulated |
| FZD10 [66,77,78] | Proliferation/migration/metastatic dissemination Cancer reoccurrence |
Tumor promoter | Upregulated |
| vitronectin, integrin a/b, lactadherin [66,77,78]; BMI1 [79]; ceramide [80], dihydroceramide |
β-catenin overexpression Tumor invasion/migration Suppressed T-cell (CD8+) recruitment Ubiquitination of histones CCA growth, migration, local invasion, and metastatic dissemination Monocyte pro-inflammatory cytokine secretion Vascular spreading-invasion/Progression of iCCA |
Tumor promoter Tumor promoter Tumor promoter |
Upregulated Upregulated Upregulated |
| CCA-derived exosomes [81,82,83] | ↑ MSC migratory behavior Formation of desmoplastic tumor stroma (↑ FAP, a-SMA, vimentin mRNA expression/Differentiation of BMSCs into CAFs to promote tumor stroma) ↑ CXCL-1, ↑ IL-6, ↑ CCL2 expression in MSCs in exposure of KMBC-EVs ↓ cytokine-induced killer cells (CIKs), ↓ perforin/TNF-a Tumor immune escape |
Tumor promoter | Upregulated |
| HSCs | |||
| MiR-195 [84] | Inhibition of tumor growth | Tumor suppressor | Downregulated |
| TAMs | |||
| Circ-0020256 [85] | Proliferation/migration/Metastatic dissemination | Tumor promoter | Upregulated |
(LY6E) lymphocyte antigen 6 family member E, (BMSCs) bone marrow mesenchymal stem cells, (FAP) fibroblast activation protein alpha, (a-SMA) alpha-smooth muscle actin, (Circ-CCAC1) cholangiocarcinoma-associated circular RNA 1, (YY1) Yin Yang 1, (CAMLG) calcium-modulating ligand, (FZD10) frizzled class receptor 10, (CXCL1) C-X-C motif ligand 1, (CCL2) chemokine (C-C motif) ligand 2, (IL-6) interleukin-6, ↑ upregulated, ↓ downregulated.