Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. As vectors for intercellular information exchange, the potential role of extracellular vesicles (EVs) in HCC formation, progression and therapy has been widely investigated. In this review, we explore the current status of the researches in this field. Altogether there is undeniable evidence that EVs play a crucial role in HCC development, metastasis. Moreover, EVs have shown great potential as drug delivery systems (DDSs) for the treatment of HCC. Exosomal miRNAs derived from HCC cells can enhance transformed cell growth in recipient cells by modulating the expression of transforming growth factor-β activated kinase-1(TAK1) and downstream signaling molecules. Furthermore, vacuolar protein sortin 4 homolog A(VPS4A) and insulin-like growth factor(IGF)-1 regulate exosome-mediated miRNAs transfer. Immune cells- derived EVs containing integrin αMβ2 or CD147 may facilitate HCC metastasis. In addition, EVs-mediated shuttle of long non-coding RNAs (lncRNAs), specifically linc- VLDLR and linc-ROR promote chemoresistance of malignant cells. Heat shock proteins (HSPs)-harboring exosomes derived from HCC tumor cells increase the antitumor effect of natural killer (NK) cells, thus enhancing HCC immunotherapy. Indeed, inhibition of HCC tumor growth has been associated with tumor cell-derived exosomes (TEX)-pulsed dentritic cells (DCs). Exosomes are also essential in liver metastasis during colorectal carcinoma (CRC) and pancreatic ductal adenocarcinomas (PDAC). Therefore, as nucleic acid and drug delivery vehicles, EVs show a tremendous potential for effective treatment against HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common incident cancer worldwide and the third leading cause of cancer death annually [1, 2]
A growing body of evidence already described that uptake of exosomes stuffed with proteins, mRNAs, miRNAs and lipids could deliver biological information that regulate the function of target cells [17, 29]
HCC-derived exosomes can transfer their miRNA contents into recipient cells, inhibit the constitutive expression of transforming growth factor-β activated kinase-1 (TAK1) and downstream signaling associated with TAK1, and lead to HCC development and metastasis
Summary
Hepatocellular carcinoma (HCC) is the sixth most common incident cancer worldwide and the third leading cause of cancer death annually [1, 2]. A growing body of evidence already described that uptake of exosomes stuffed with proteins, mRNAs, miRNAs and lipids could deliver biological information that regulate the function of target cells [17, 29] This mechanism may explain how exosomes mediate tumor progression and metastasis. HCC-derived exosomes can transfer their miRNA contents into recipient cells, inhibit the constitutive expression of TAK1 and downstream signaling associated with TAK1, and lead to HCC development and metastasis. The uptake of exosomes from invasive HCC cell lines can trigger the activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogenactivated protein kinase (MAPK) signaling pathways, which resulting in increased secretion of active MMP, enhanced migratory and invasive abilities of non-motile immortalized hepatocytes [24] This may potentially lead to increased protrusive activity of HCC cells through the liver parenchyma during the process of metastasis. Exosomal transfer of VASN from HCC cells promotes mobility properties in hepatic endothelial cells, inducing cancer cell migration to the surrounding tissue [53](Table 1)
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