Table 1.

Liver parenchyma derived EVs in HCC development.

EV Content	Donor Cell	Recipient Cell	Function	References
Tumour initiation
miR-122	Normal cells	T-ICs	Inhibit tumour initiation and maintains homeostasis	[134]
IGF1	T-ICs	Normal cells	Prevents miR-122 production leading to tumour initiation	[134]
mir-584, miR-517c, miR-378, miR-520f, miR-142-5p miR-451, miR-518d, miR-215, miR-376a, miR-133b, miR-367	HCC cells	Normal cells	Modulate the expression of TGF-B-activated kinase 1 and associated signalling molecules resulting in transformation of recipient cells	[135]
miR-429	T-ICs	Normal cells	Induces liver T-ICs properties on normal cells and thus facilitates HCC formation via RBPP4/E2F1/OCT4 axis	[136]
Tumour growth
TUC339	HCC cells	HCC cells	Enhance proliferation	[137]
Angiogenesis
lncRNA H19	Hepatoma cells	Endothelial cells	Increase the VEGF production	[139]
miR-210-3p	HCC cells	Endothelial cells	Promotes the in vivo tubulogenesis of endothelial cells and the in vivo angiogenesis of HCC by inhibiting the expression of SMAD4 and signal transducer and activator of transcription in endothelial cells	[140]
Vasorin	HCC cells	Endothelial cells	Accelerates the migration of endothelial cells	[141]
Unknown	HCC cells	HUVEC cells	Potentiates tumour angiogenesis via tube formation of HUVEC cells and growth of vessels by plugs assays on nude mice	[142]
Delta-like ligand 4	Endothelial cells	Endothelial cells	Promote angiogenesis by blocking the Notch signal	[143]
Invasion
MET protein, caveolins, S100	HCC cells	HCC cells	Recipient cells acquires migratory and invasive abilities	[144]
CD147	HCC cells	Fibroblast	Secretes MMP-2, a protein involved in matrix degradation	[145]
Metastasis
miR-103	Hepatoma cells	Endothelial cells	Inhibits the expression of VE-cadherin, p120-catenin and ZO-1 to attenuate the integrity of endothelial junctions and induce vascular leakiness	[149]
mir-1247-3p	HCC cells	Fibroblast	Conversion of fibroblast into cancer associated fibroblasts in the lung PMN	[150]
Innate molecules	Innate immune cells	HCC cells	Increases the metastatic potential of recipient cell	[151]
α6β4 and α6β1 integrins	HCC cells	Fibroblasts Epithelial cells	Dictates the fate of future metastasis	[152]

HCC, hepatocellular carcinoma; T-ICs, tumour initiating cells; HUVEC, human umbilical vein endothelial cells; MMP-2, matrix metalloproteinase-2; lncRNA H19, long non-coding RNA H19.