Small extracellular vesicles promote the formation of the pre-metastatic niche through multiple mechanisms in colorectal cancer

Figures & data

Figure 1. The role of sEVs derived from CRC in the formation of pre-metastatic niche.

Table 1. sEvs promote upregulation of inflammatory factors in the pre-metastatic niche of colorectal cancer.

Characteristic	sEVs cargos	Tissues and/or cells	Mechanism and function	Refs
Inflammation	miR-6803-5p	HCT116	Promotes cancer cell proliferation and invasion through the PTPRO/NF-κB axisin colorectal cancer and enhances inflammation	25
Inflammation	ITGBL1	HCT116’Caco2, LoVo, SW480, SW620; plasma from CRLM; CRC tissues	Stimulation of TNFAIP3-mediated NF-κB signaling pathway activates fibroblasts,and activated fibroblasts secrete pro-inflammatory cytokines	27
Inflammation	microRNA-21-5p (miR-21)	SW480, SW620; plasma;CRC tissues	Polarization of hepatic macrophages to an interleukin il −6 producingphenotype via TLR7 induces the formation of an inflammatory microenvironment	28
Inflammation	integrins	HT29	Up-regulation of pro-inflammatory S100 molecule expression in the distal tissue microenvironment	29

Table 2. sEvs promote immunosuppression in pre-metastatic niche of colorectal cancer.

Characteristic	immune cell	sEVs cargos	Tissues and/or cells	Mechanism and function	Refs
Immunosuppression	TAM	miRNAs (miR-25-3p,miR-130b-3p,miR-425-5p)	HCT116’SW620	activation of PI3K/Akt signaling pathway regulates PTEN, induces M2 polarization in macrophages, enhances EMT and secretion of VEGF.	37
Immunosuppression	TAM	miR-145	DLD-1	the downregulation of histone deacetylase 11 ’polarized macrophage-like cells into the M2-like phenotype	38
Immunosuppression	TAM	miR-203	plasma	Induce macrophage M2 polarization to promote the formation of PMN	39
Immunosuppression	TAM	miR-934	HCT-8’LoVo’HT-29’Caco-2; plasma; CRC tissues	Downregulation of PTEN expression and activation of PI3K/AKT signaling pathway induce M2 macrophage polarization, and secretion of CXCL13 promotes the formation of PMN	40
Immunosuppression	TAM	lncRNA RPPH1	HCT8’SW620’HT29; CRC tissues	RPPH1 induces EMT in CRC cells by interacting with TUBB3; CRC cell-derived exosomes translocate RPPH1 into macrophages and mediate macrophage M2 polarization	41
Immunosuppression	TAM	miR-106	Plasma;HCT116(EMT-CRC)	Activation of PI3Kγ/AKT/mTOR signaling pathway to promote the polarization of M2 macrophages	42
Immunosuppression	TAM	miR-1246	HCT116’DLD-1’HT29’H358	Colon cancer cells with GOF mutp53 promote the formation of unique reprogrammed macrophage populations by releasing miR-1246-containing exosomes	44
Immunosuppression	TAM	lncRNAs	HT29(BRAF^V600E mutant’;CRC tissues	Promotes macrophage polarization to the M2 subtype and enhances the secretory function of macrophages and fibroblasts, and induces the formation of an immunosuppressive microenvironment	47
Immunosuppression	TAM	tRF-3022b	CRC tissues; Plasma	Reduced M2 macrophage polarization by binding to LGALS1and MIF	48
Immunosuppression	TAM	miR-1827	human umbilical cord mesenchymal stem cells	Down-regulation of SUCNR1 expression inhibits M2 macrophage polarization	49
Immunosuppression	TAM	CCL2	MC38 cell	Activated macrophage recruitment and shifted the M1/M2 paradigm to a M2 phenotype	50
Immunosuppression	TAM	miR-155-5p	M2 macrophages	Downregulation of ZC3H12B increases IL-6 expression in the ground to promote immune escape in colon cancer	51
Immunosuppression	TAN	circPACRGL	HCT116’SW480	Promotes neutrophil N2 polarization via miR-142-3p/miR-506-3p-TGF-β1 axis, leading to immune escape of tumors	56
Immunosuppression	TAN	mutant KRAS	DKs-8 (WT allele), DKO-1 (KRAS mutant)	Increases IL-8 production, promotes neutrophil recruitment and NET formation, and promotes metastatic and invasive capabilities	58
Immunosuppression	TAN	has-miR-4780’has-miR-3938	CRC tissues	Promotes neutrophil N2 polarization, regulates both TUSC1 and ZNF197 genes, and affects CRC invasion and metastasis	59
Immunosuppression	Treg	TGF-β1	DLD-1’WiDr	CRC-EVs induced phenotypic alteration of the T cells to Treg-like cells through activating TGF-β/Smad signaling and inactivating SAPK signaling.	65
Immunosuppression	Treg	miR-208b	SW480;SW480-OXA;NCM460;CT26	Targeting PDCD4 promotes Treg amplification, thereby promoting immunosuppression	66
Immunosuppression	MDSC	S100A9	G-MDSCs	Hypoxia upregulates HIF-1α to promote the production of sEVs by G-MDSCs, and MDSC-sEVs exacerbate the stemness of colorectal cancer cells by releasing S100A9	77

Table 3. sEvs increase angiogenesis and vascular permeability in the pre-metastatic niche of colorectal cancer.

Characteristic	sEVs cargos	Tissues and/or cells	Mechanism and function	Refs
Angiogenesis and Vascular Permeability	miR-92a-3p	DLD-1’WiDr’COLO201’SW480	Reducing Dickkopf-3 and Claudin-11 expression in HUVECs induces partial endothelial-to- mesenchymal transition in endothelial cells, thereby promoting angiogenesis	82
Angiogenesis and Vascular Permeability	miR-25-3p	NCM460’SW480’LS174T’SW620’LOVO’HCT116	Disrupts the integrity of the endothelial barrier and induces angiogenesis, thereby promoting hepatopulmonary metastasis of CRC	83
Angiogenesis and Vascular Permeability	microRNA-135b-5p	LoVo’HT29	Inhibition of thioredoxin-interacting proteins promotes colorectal cancer cell growth and angiogenesis	84
Angiogenesis and Vascular Permeability	miR-1229	plasma; CRC tissues	Targeting HIPK2 promotes angiogenesis, thereby facilitating the formation of pre-metastatic ecotone	85
Angiogenesis and Vascular Permeability	Wnt4	HT29	Mediating β-catenin pathway conduction promotes angiogenesis in endothelial cells	86
Angiogenesis and Vascular Permeability	miR-21-5p	Lovo;SW620;HT29;SW480;HCT116;LS174T; plasma;CRC tissues	Targeting KRIT1 activates the β-linked protein signaling pathway, thereby inducing angiogenesis and vascular permeability	87
Angiogenesis and Vascular Permeability	miR-183-5p	FHC;DLD-1;HT29;HCT116;HMEC-1;NCI-H508	Targeting FOXO1 enhances angiogenesis in microvascular endothelial cells	88
Angiogenesis and Vascular Permeability	lncRNA-APC1	HCT116, DLD-1, SW480, LOVO, SW1116 and CRC tissues	Exosomes from CRC cells with lncRNA-APC1 silencing promote angiogenesis by activating the MAPK pathway in endothelial cells	89
Angiogenesis and Vascular Permeability	circTUBGCP4	HCT116;SW480 and plasma	Inhibition of miR-146b-3p promotes tip cell formation and activates the Akt signaling pathway to promote angiogenesis	90
Angiogenesis and Vascular Permeability	ANGPTL1	CRC tissues	Inhibition of JAK2-STAT3 signaling pathway, reprogramming of Kupffer cells and reduction of MMP9 expression to block vascular leakage in hepatic PMN, thereby attenuating CRC liver metastasis	91

Table 4. Other roles of sEvs in the pre-metastatic niche.

Characteristic	sEVs cargos	Tissues and/or cells	Mechanism and function	Refs
Lymphangiogenesis	IRF-2	CT26	Inducing macrophages to release VEGFC, thus promoting the proliferation of lymphatic endothelial cells and the formation of lymphatic network in SLN, and promoting SLN metastasis in colorectal cancer	95
Lymphangiogenesis	miR-302d-3p	Human Umbilical Cord Mesenchymal Stem Cells	Targeting FLT4 to inhibit lymphangiogenesis and macrophage infiltration to improve IBD	96
Organotropism	ITGα v β 5	HT29	Binds to Kupffer cells and mediates hepatophilic	29
Organotropism	ITGα 6 β 4’ ITGα 6 β 1	HT29	Binding of lung-resident fibroblasts and epithelial cells to control pulmonary eosinophilia	29
Organotropism	-	HT29 and Caco2	be associated with the SDF-1/CXCR4 axis	97
Organotropism	miR-135a-5p	CRC tissues	The hypoxic microenvironment in primary CRC lesions promotes the release of sEVs, which are phagocytosed by Kupffer cells into the liver’and miR-135a-5p^+sEVs initiate the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the development of CRC liver metastases	98
Reprogramming	-	SW480;SW620	sEVs activate fibroblasts and invade the extracellular matrix, thereby advancing metabolic reprogramming	104
Reprogramming	HSPC111	HCT116’ HT29’SW480, SW620; CRC tissues	Reprogramming lipid metabolism in cancer-associated fibroblast CAF promotes pre-metastatic ecotone formation and liver metastasis in colorectal cancer	106
EMT	miR-128-3p	HCT116,SW480	miR-128-3p^+sEVs regulates EMT by directly suppressing its downstream target gene FOXO4 to activate TGF-β/SMAD and JAK/STAT3 signaling, and the properties of the miR-128-3p/FOXO4 axis were horizontally transferred via exosomal delivery.	113
EMT	circCOL1A2	HT29, HCT116, LOVO, SW480, and SW620	circCOL1A2^+sEVs mediated miR- 665/LASP1 axis to affect the EMT and modulate CRC progression	114
EMT	PCAT1	HCT116,SW480	lncRNA PCAT1 Promotes Tumor Circulating Cell-Mediated Colorectal Cancer Liver Metastasis by Regulating the Activity of the miR-329-3p/Netrin-1-CD146 Complex	115
EMT	miR-335-5p	SW480,SW620	sEVs-encapsulated miR-335-5p promotes CRC cell invasion, metastasis, and EMT transition by directly targeting RASA1	116