Table 2 Summary of the major biological mechanisms influenced by extracellular vesicles, their key biomarker candidates, and biological effect in the tumor microenvironment
Biological mechanism | Key EV biomarker | Biological effect in the tumor microenvironment | References |
|---|---|---|---|
Potentiating tumor progression | TGFß miR-210 miR-125b miR-630 | CAF activation and promoting tumor growth. | |
miR-21 miR-378e miR-143 | Promoting epithelial to mesenchymal transition and stem cell-like traits. | ||
Establishing a premetastatic niche | Fibronectin Collagens Laminins TGFβ | Extracellular matrix degradation. Tumor migration, invasion, and metastasis. | |
Integrin α6β1 Integrin α6β4 Annexin A6 ITGBL1 miR-105 miR-122 | Lung metastasis | ||
Integrin αVβ5 miR-200 ITGBL1 EGFR | Liver metastasis | ||
miR-19a miR-122 miR-105 CEMIP | Brain metastasis | ||
miR-19a miR-152-3p | Bone metastasis | ||
Inducing tumor angiogenesis | CD39 CD73 VEGF (VEGF189 in small EVs; VEGF90K in microvesicles) MMPs FGF uPA IL-6 miR-17-5p miR-205 miR-27a miR-105 | Direct interaction with endothelial cells to regulate angiogenesis. Promoting the secretion of proangiogenic factors. Reprogramming immune cells (e.g., mast cells and macrophages), via adenosine signaling, to release proangiogenic factors. | |
Caveloin-1 Ceramides | Inducing the release of EVs containing proteins and lipids that modulate endothelial cells. | ||
Regulating tumor immune response | |||
Modulating macrophage activity | miR-21-3p miR-181d-5p miR-125b-5p miR-29a-3p miR-146a-5p miR-222 Anx II gp130 | Promoting macrophage polarization towards the pro-tumoral M2 phenotype. | |
Modulating myeloid-derived suppressor cells activity | PD-L1 PGE2 TGFβ HSP70 miR-181a miR-9 miR-21a miR-1246 | Inducing the differentiation of immature myeloid cells into MDSCs. ⚬ STAT3 activation and inhibition of SOCS3 and PIAS3. ⚬ Downregulation of PDCD4 protein. ⚬ Inducing DUSP3 enzyme activity in ERK-dependent manner. | |
miR-155 miR-494 miR-233 miR-690 miR-126a | Expansion and activation of MDSCs. | ||
Modulating T cell activity | TGFβ1 IL-10 CCL20 miR-24–3p Arginase 1 Fas ligand TRAIL Galectin-1 Galectin-9 | Inhibition of CD8+ T-cells. Promoting Treg expansion. Inducing T cell exhaustion. ⚬ Downregulation of signaling components related to T cell activation (e.g., JAK3 and CD3ζ). ⚬ Upregulation of inhibitory molecules (e.g., PD-L1, CTLA4, TIM3, LAG-3, and TIGIT). | |
Modulating dendritic cell activity | Galectin-9 HSP72 HSP105 ARG1 PGE2 MALAT1 miR-212-3p | Inhibition of dendritic cell antigen presentation function. | |
Fatty acids | Inducing immunologically dysfunctional dendritic cells. ⚬ Enhancing oxidative phosphorylation of mitochondria via the peroxisome proliferator-activated receptor (PPAR)α. | ||
PD-L1 and other EV cargoes | Inhibition of dendritic cells maturation. ⚬ Shifting the differentiation of dendritic cells towards MDSCs and M2 macrophages. ⚬ Downregulation of costimulatory molecules of CD83 and CD86. | ||
Modulating natural killer cell activity | NKG2D ligand-expressing EVs (containing MICA*008) TGFβ1 | Inhibition of NK cells activity. ⚬ Promoting a higher expression of the inhibitory receptor NKG2A. ⚬ Downregulation of the activating receptors NKG2D and NKp44. | |
Modulating neutrophil activity | TEV: KRAS-mutated exosomes HMGB1 | Promoting neutrophil migration. Inducing the formation of neutrophil extracellular traps. Inducing a pro-tumor phenotype in neutrophils. | |
Neutrophil derived EVs: FGF-1 MMP-2 MMP-9 CD66c Lipocalin2 Myeloperoxidase S100A8/9 | Reprogramming the activity of neutrophils towards the pro-tumoral N2 phenotype. ⚬ Facilitating tumor progression, angiogenesis, and immune evasion. | ||
Remodeling metabolic activity | Cholesterol Phosphatidylserine Phosphatidylcholine Phosphatidylinositol Leukotrienes Prostaglandins Arachidonic acid Eicosanoïds FASN | Promoting tumor progression and metastasis. Facilitating immune evasion. ⚬ T cell inhibition. | [231, 167, 197, 260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280] |
Unsaturated diacylglycerol | Promoting neo-angiogenesis and tumor progression ⚬ Inducing protein kinase D signaling pathway in endothelial cells. | ||
FASN Fatty acid transporters: Fatty acid binding proteins Acyl-CoA binding proteins Carnitine palmitoyltransferase 1A CAF-associated EVs: Tricarboxylic acid cycle metabolites, including amino acids (e.g., glutamine, arginine, glutamate, proline) and metabolites required for lipid synthesis (e.g. acetate) | Fatty acid β-oxidation. Promoting proliferation of cancer cells and maintain their source of energy. Facilitating immune evasion. ⚬ Inducing dysfunctional dendritic cells. | ||
Glycolytic enzymes Lactate dehydrogenase CD39 CD73 | Aerobic glycolysis / Warburg effect. Reducing the availability of glucose. Elevating free ATP and lactate levels in the TME. Inducing adenosine signaling. Facilitating immune evasion, angiogenesis, and tumor growth. ⚬ Inducing MDSC expansion. ⚬ Inhibiting cytotoxic T and NK cells. ⚬ Reprogramming macrophages and endothelial cells towards an angiogenic phenotype. | ||