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Page 8 of 12 Jayachandran et al. Hepatoma Res 2018;4:44 I http://dx.doi.org/10.20517/2394-5079.2018.59

Chemoresistance
Cell behaviour can be modulated by the content within exosomes during chemotherapeutic treatment in HCC
cells. For example, exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and
doxorubicin increased the lncRNA, linc-VLDRL within the exosomes released from these treated cells and
promoted chemotherapeutic resistance . Another study explored how transforming growth factor (TGF)-β
[59]
selectively enriched lncRNA linc-RoR within exosomes and thereby facilitated chemoresistance . Treating
[59]
HepG2 and Hep3B cells with miR-122 loaded exosomes derived from adipose tissue derived mesenchymal
stem cells (ADMCs) sensitised these cells to doxorubicin and sorafenib . Furthermore, a study found
[49]
that exosomes derived from HCC cells can block the therapeutic effects of sorafenib and promote tumor
growth . This study demonstrated that exosomes derived from highly invasive hepatoma cells, MHCC-97
[60]
L and MHCC-97H had greater efficacy than that of exosomes derived from less invasive cells, LO2. Notably,
combined treatment with sorafenib and exosomes derived from highly invasive hepatoma cells resulted
in the formation of larger tumours in mice than those in mice treated with sorafenib alone or sorafenib
plus exosomes derived from less invasive cells . After treatment with conditioned media collected from
[60]
fibroblasts pre-treated by exosomes derived from high-metastatic cancer, tumour cells showed increased
spheroid formation ability, motility, and resistance ability to sorafenib . Thus, exosomes can modulate
[19]
chemoresistance in recipient cells that incorporate these exosomes. Understanding how exosomes confer
resistance to cellular stress will enable us to develop more effective treatments for HCC.

Cancer stem cells
Accumulating evidence implicates cancer stem cells (CSCs) in the growth and spread of HCC . CSCs
[61]
have the capacity for self-renewal and ability to differentiate, and have been identified to confer resistance
to chemotherapy. Exosomes have been implicated in promoting stemness in HCC. For example, TGF-β
treatment enhanced the growth of CD133+ CSCs in HepG2 cells. Both stemness and chemoresistant
phenotype of CSCs were modulated by lncRNA linc-RoR within the exosomes derived from TGF-β treated
cells . SMMC-7721 cells treated with miR-12473p revealed increased sphere formation with elevated
[59]
expression in CSC marker genes such as CD133, lrg5, Oct4, nanog and CD90 .
[19]

Epithelial-to-mesenchymal transition
Epithelial-to-mesenchymal transition (EMT) is a cellular process during which epithelial cells undergo a
phenotypic switch to become more aggressive and motile mesenchymal cells . The process of EMT is also a
[62]
major contributor for metastasis and drug resistance . More recently, exosomes have been described to mediate
[61]
EMT in many cancers . In HCC cell lines, the expression of miR-320a was significantly downregulated and
[63]
induced EMT as evidenced by changes in EMT marker expression. miR-320a simultaneously enhanced
the expression of mesenchymal marker, N-cadherin and suppressed the expression of epithelial marker
E-cadherin, thereby eliciting EMT .
[44]

DISCUSSION
Numerous studies suggest clinical usefulness of exosomes as minimally invasive biomarkers for the
detection, diagnosis and prognosis of different cancers [9,10] . In HCC, there is poor consensus regarding the
use of exosome-derived miRs as diagnostics. This could be ascribed to diversity of study designs, analytical
conditions, choice of internal control genes, choice of body fluid used such as serum or plasma, choice of
control and patient populations and sample size . Furthermore, most of the data reported in HCC literature
[17]
have been obtained on eastern patients, whose tumour biology might not match that of western patients.
Indeed, obtaining exosome-based liquid biopsies might prove to be beneficial in cases where obtaining
tumour biopsies is difficult in clinical settings. However, it is still necessary to standardise methods for
exosome isolation and characterisation by using guidelines proposed by the EV-TRACK Consortium .
[64]
Furthermore, the potential use of exosomes as delivery vector needs more critical evaluation.