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Jayachandran et al. Hepatoma Res 2018;4:44 I http://dx.doi.org/10.20517/2394-5079.2018.59 Page 7 of 12

which tumour cells can promote HCC growth and spread . Thus, the use of exosomes as biological delivery
[55]
vehicles is of considerable interest.

Modulation of HCC tumour growth and metastasis
Exosomes are considered to serve essential roles in tumour growth and metastasis by regulating complex
interactions between tumour cells and their microenvironment. Several studies addressed whether HCC
cell-derived exosomes can influence the biological behaviour of the parental HCC cells. A study revealed
that incubation of SMMC-7721 cells with self-derived exosomes caused a notable increase in cell growth,
migration, and invasion . Another study described a comprehensive RNA and protein profiling of
[15]
exosomes derived from motile and non-motile HCC cell lines. Exosomes derived from metastatic HCC cell
lines HKCI-C3, HKCI-8 and MHCC97L were enriched in protumorigenic RNAs and proteins, such as MET
protooncogene, S100 family members and the caveolins. Of interest, exosomes from motile HCC cell lines
could significantly enhance the migratory and invasive abilities of non-motile immortalised hepatocyte line
MIHA. Motile behaviour in MIHA cells was triggered by activation of PI3K/AKT and MAPK signalling
pathways which in turn increased secretion of active matrix metalloproteinase, MMP-2 and MMP-9 . A
[56]
comparative proteome analysis of exosomes from the non-motile Hep3B cell, and the motile 97H and LM3
cells found the motile HCC cells to secrete more sugar metabolism regulatory proteins via exosomes in the
tumour microenvironment . The ability of exosomes to modulate the motile ability of tumour cells was
[28]
tested by comparing protein profiles of cell lines with distinct metastatic potential. Among these, adenylyl
cyclase associated protein 1, a protein implicated in HCC metastasis, was significantly enriched in exosomes
from cells with high motile ability. Moreover, incubating low motile MHCC97 L cells with highly motile
MHCC97 H cell-derived exosomes, enhanced the motile ability of MHCC97-L cells . Thus, it is conceivable
[57]
that highly motile HCC cell-derived exosomes could modify normal hepatocytes and less motile HCC cells
in their microenvironment to facilitate tumour growth, invasion and metastases.

Alteration in exosomal miRs also influences tumour behaviour. For instance, HCC cell-derived exosomes
have been shown to activate the MAPK/ERK pathway through miR-665 and further promote the proliferation
of tumour cells . Whereas, the expression of miR-320a was significantly downregulated in HCC cell
[40]
lines. miR-320a binds to its direct downstream target and suppresses HCC cell proliferation, migration
and metastasis . Previous studies have shown that the increase of mast cells (MCs) usually indicates a
[44]
poor prognosis of HCC patients . MC-derived exosomes showed increased expression of miR-490 and the
[58]
transfection of HepG2 and Hep3B cells with these exosomes inhibited migration and invasion in both the
HCC cell lines . Exosomes derived from high-metastatic cancer cells contribute to fibroblast activation to
[29]
foster lung metastasis of liver cancer via transfer of miR-1247-3p .
[19]

Immune modulation
Emerging evidence suggests that HCC-derived exosomes can mediate dialogue between cancer cells and
immune cells to promote antitumor immune responses for tumour growth. For instance, Wang et al.
[32]
demonstrated that 14-3-3ζ, also called 14-3-3 protein zeta was transmitted from HCC cells to T cells via
exosomes and resulted in the inhibition of anti-tumour functions of tumour-infiltrating T cells in the HCC
microenvironment. HCC–derived exosomes have been shown to be enriched in HCC antigens, which in
turn can prime cytotoxic T lymphocytes and elicit a stronger immune response in vitro and in vivo compared
with cell lysates . Exosomes from HCC cells can also present tumour antigens to versatile mediators of the
[4]
immune system, the dendritic cells to induce a strong immune response and to suppress tumour growth .
[4]
Similarly, another study combined tumour-derived exosome-pulsed dendritic cells and PD-1 antibody with
sorafenib and observed the effects on tumours in mice with orthotopic HCC. This treatment combination
induced antitumor responses and changed the tumour microenvironment by decreasing T regulatory cell
accumulation in tumour tissue after sorafenib treatment .
[31]