Table 1.
EV cargoes associated with CRC metastasis
| EV cargo | Producing cells | Expression patterns | Target cells | Related genes and/or pathways | Function/outcome | References |
|---|---|---|---|---|---|---|
| Regulation of EMT | ||||||
| Non-coding RNAs | ||||||
| miR-106b-5p | CRC cell lines | Increased | Macrophages | Triggers M2 macrophage polarization via downregulation of PDCD4 and activation of PI3Kg/AKT/mTOR signaling | Induction of EMT; facilitates liver and lung metastasis in mice | [10] |
| miR-21-5p and miR-155-5p | M2 macrophages | Increased | CRC cell lines | Attenuates tumor suppressor BRG1 | Increased migration and invasion | [43] |
| miR-146a-5p | CRC cells overexpressing CXCR7 | Increased | CAFs | Promotes CAF activation by attenuating ZBTB2 expression and subsequently activating NF-kB signaling | Activation of CAFs; Promotes invasion and EMT | [40] |
| miR-155-5p | CRC cells overexpressing CXCR7 | Increased | CAFs | Promotes CAF activation and cytokines release by suppressing SOCS1 expression and inducing JAK/STAT3 signaling | Activation of CAFs; Promotes invasion and EMT | [40] |
| lncRNA RPPH1 | CRC cell lines | Increased | CRC cells; human monocyte-derived macrophages | Binds to β-III tubulin (TUBB3) and prevents its ubiquitination in CRC cells | Promotes invasion and EMT; induction of M2 macrophage polarization | [39] |
| miR-92a-3p | CAFs | Increased | CRC cells | Induction of Wnt/β-catenin signaling and inhibition of mitochondrial apoptosis through downregulation of FBXW7 and MOAP1 | Enhances stemness and EMT; liver metastasis; induction of chemoresistance to 5-FU/oxaliplatin | [34] |
| MiR-186-5p | M2 macrophage | Increased | Colon cancer cells | Inhibition of DLC1 expression and activation of the β-catenin pathway | Stimulates tumor cell growth and motility | [42] |
| lncRNA LINC00659 | CAFs | Increased | CRC cells | Sponges miR-342-3p to increase annexin A2 (ANXA2) | Increased proliferation, invasion, migration, and EMT | [45] |
| Proteins | ||||||
| FZD10 | colon cancer cell lines | Increased | Colonic epithelial cells | Induction of Wnt/β-catenin signaling | Promotes EMT; enhances cancer cell viability and proliferation | [37, 38] |
| Wnt | Macrophages | Increased | NA | Activation of Wnt/β-catenin | Maintenance of intestinal stem cells; increased intestinal repair after radiation in mice | [35] |
| Premetastatic niche formation | ||||||
| Non-coding RNAs | ||||||
| miR-25-3p | CRC cell lines | Increased | Human umbilical vein endothelial cells (HUVEC) | Increases expression of VEGFR2 and reduces tight junction proteins ZO-1, occluding, and Claudin5 by silencing KLF2 and KLF4 | Increased vascular permeability; angiogenesis; liver and lung metastasis in mice | [48] |
| miR-320c | Blood sample of metastatic CRC patients; CRC cell lines | Increased | NA | NA | Promotes mesenchymal-epithelial transition (MET) in metastasized cells; formation of PMN | [52] |
| miR-934 | CRC cells | Increased | Macrophages; human Kupffer cells | Promotes M2 macrophage polarization by attenuating PTEN and inducing PI3K/AKT signaling; M2 macrophages facilitate liver metastasis through CXCL13/CXCR5 axis | M2 macrophage polarization; liver metastasis | [53] |
| miR-181a-5p | highly metastatic CRC cells | Increased | Hepatic stellate cells (HSCs) | Activation of HSCs by downregulating SOCS3 and inducing IL6/STAT3 signaling | Liver metastasis | [51] |
| miR-21 | CRC cells | Increased | Liver macrophages; human macrophage cell line | Activates Toll-like receptor 7 (TLR7) in liver macrophages | Macrophage polarization toward IL-6 secreting phenotype; induction of inflammatory PMN in the liver | [64] |
| miR-135a-5p | CRC cells; Serum of CRC patients; tumor tissues from CRC patients | Increased | Kupffer cells | Impedes tumor suppressor kinase LATS2 expression, and subsequently activates YAP1/TEAD1 complex and elevates MMP7 expression | mice liver metastasis; inhibition of CD30-mediated CD4 + T cells activation; Increased cell adhesions; PMN formation | [54] |
| Proteins | ||||||
| Integrin beta-like 1 (ITGBL1) | Tumor tissues from CRC patients; plasma sample of CRC patients; CRC cell lines | Increased | Hepatic fibroblasts; hepatic stellate cells | Binds to TNFAIP3 and triggers the NF-κB signaling pathway | Fibroblast activation; increased secretion of proinflammatory cytokines; PMN formation | [63] |
| RNA binding protein HuR | CRC cell line | Increased | Bronchial epithelial cells | Stabilizes c-Myc and downregulates p21 expression | Increased proliferation, migration, and invasion of bronchial cells | [66] |
| Interferon regulatory factor 2 (IRF2) | Mouse colon carcinoma cells; blood samples of CRC patients | Increased | Macrophages | Increased secretion of VEGF-C from macrophages | Lymph node metastasis | [49] |
| TGF-β1 | CRC cells | Increased | Hepatic stellate cells (HSCs) | Provokes HSCs differentiation into CAFs via Activation of HSCs chemokines signaling; Utilizes MDSCs into the liver; abrogates NK cell cytotoxicity by repressing NKG2D | Facilitates premetastatic immunosuppressive niche in the liver; inhibition of NK cell cytotoxicity; induction of HSCs differentiation into CAFs | [55] |
| HSPC111 | CRC cell lines | Increased | HSCs cell line | Education of HSCs into CAFs; interacts with ATP-citrate lyase (ACLY), resulting in accumulation of acetyl-CoA in CAFs; promotes CXCL5 secretion by increasing H3K27 acetylation | PMN formation and liver metastasis; impedes the lipid metabolism of CAFs; | [65] |
| Angiogenesis | ||||||
| Non-coding RNAs | ||||||
| miR-1229 | Tumor tissues and blood samples from CRC patients; CRC cell lines | Increased | HUVECs | Inhibition of HIPK2 protein expression; promotes MEF2C-mediated activation of VEGF | Facilitates proliferation, migration, and tube formation of HUVECs | [70] |
| miR-183-5p | CRC cell lines | Increased | Human endothelial cells (HMEC-1) | Decreased FOXO1 expression | Facilitates proliferation, migration, and tubulogenesis of HMEC-1 | [71] |
| miR-21-5p | CRC cells | Increased | HUVECs | Reduced Krev interaction trapped protein 1 (KRIT1) expression; increased activation of the β-catenin signaling pathway, and upregulation of downstream VEGFa and Ccnd1 | Angiogenesis; increased vascular permeability | [72] |
| miR-181a-5p | BAP31-overexpressing CRC cells | Increased | human lung normal fibroblast cells; mouse embryonic fibroblast cells | Silences reversion-inducing cysteine-rich protein with kazal motifs (RECK); upregulation of MMP-9 and phosphorylation of Smad2/3 | Differentiation of fibroblasts into proangiogenic CAFs; angiogenesis | [75] |
| Proteins | ||||||
| Wnt4 | Hypoxic CRC cells | Increased | HUVEC | Wnt/β-catenin signaling | Promotes tumor growth and angiogenesis in vitro and in vivo | [69] |
| Gas6 | Tumor perivascular cells | Increased | Endothelial progenitor cells | Employs endothelial progenitor cells through activation of the Axl pathway | Instigates cancer revascularization after antiangiogenic therapy withdrawal | [73] |
| VEGFA | Chemoresistant CAFs | Increased | CRC cells | VEGFA | Provokes proliferation, cisplatin resistance, and angiogenesis of CRC | [83] |
| Angiopoietin-like protein 1 (ANGPTL1) | CRC cell line | Decreased | Mouse Kupffer cell line | Downregulates MMP9 expression in KCs via inhibition of JAK2-STAT3 signaling | Attenuates vascular leakiness and hinders liver metastasis | [77] |
| Tumor cells proliferation | ||||||
| miR-6819-5p, miR-6737-5p, and miR-1249-5p | TP53 mutant colon cancer cells | Increased | Human colon fibroblasts; human lung fibroblasts | Decreased TP53 expression in fibroblasts | Instigates fibroblast‐mediated tumor growth; enhances fibroblast proliferation | [85] |
| miR-193a | Mouse colon carcinoma cells; human colon cancer cells | Increased in serum exosomes; decreased in CRC cells | NA | Sorting of tumor-suppressor miR-193a out of cells leads to tumor growth through; inhibition of Caprin1 and downstream targets cyclin D2 and c-MYC | Inhibits tumor progression | [86] |
| miR-486-5p | CRC tissues and cell lines; Plasma specimens from CRC patients | Increased in serum exosomes; decreased in CRC cells | NA | Exosomal packaging of tumor-suppressor miR-486-5p out of cells;downregulation of PLAGL2 and downstream β-catenin and IGF2 signaling | Inhibits proliferation and migration in vitro and in vivo | [87] |
| miR-361-3p | Hypoxic CRC cells | Increased | CRC cells | Targets TNF receptor-associated factor 3 (TRAF3) and promotes noncanonical NF‐κB signaling | Decreased apoptosis and increased proliferation | [88] |
| lncRNA UCA1 | CRC tissues and cell lines; blood samples from CRC patients | Increased | CRC cells | Sponges miR-143 and escalates MYO6 expression | Accelerates proliferation and migration in vitro and in vivo | [89] |
| circIFT80 | CRC tissues and cell lines; blood samples from CRC patients | Increased | CRC cells | Sponges miR-1236-3p and escalates HOXB7 expression | Instigates proliferation, migration, and EMT | [90] |
| circFMN2 | CRC cells; CRC tissues; blood samples from CRC patients | Increased | CRC cells | Acts as a sponge for miR-1182 and elevates hTERT expression | Increased proliferation and migration | [91] |
| circPACRGL | CRC cells | Increased | CRC cells; polymorphonuclear neutrophils | Sponges miR-142-3p and miR-506-3p and elevates TGF-β1 expression | Increased progression and migration; N2 neutrophil differentiation | [92] |
| circRHOBTB3 | CRC cell lines; tissues and sera of CRC patients | Increased in serum exosomes; decreased in CRC tissues | NA | Excretion of tumor-suppressor circRHOBTB3 out of cells; regulation of intracellular ROS levels and metabolic enzymes ENO1 and ENO2 | Inhibition of CRC cell proliferation and EMT in vitro and in vivo | [93] |