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Page 2 of 12 Jayachandran et al. Hepatoma Res 2018;4:44 I http://dx.doi.org/10.20517/2394-5079.2018.59

radiotherapeutic interventions are intensively used in the clinic; however, the survival benefit is limited .
[4]
The poor prognosis of advanced HCC is, in part, related to the lack of reliable biomarkers for early diagnosis
and the lack of effective therapeutic agents for unresectable tumours. Currently, the clinical diagnosis of HCC
relies on serum alpha-fetoprotein (AFP) levels and imaging examination, including ultrasound, computed
tomography (CT), magnetic resonance imaging (MRI), and invasive tumour biopsy . However, it is widely
[5]
known that these screening methods have low sensitivity, high false negative rates and cannot predict post-
therapy recurrence and also fail to monitor real time disease and therapy . Furthermore, conventional
[6,7]
tumour biopsies provide a small sample size and may fail to reflect the entire tumour heterogeneity that is
essential in treatment procedures and prescribing a targeting therapy based on the genotype. Therefore, to
improve the prognosis and survival of HCC patients, there is an urgent need for more sensitive and effective
tools for early detection, screening, real time monitoring of the disease and prognosticating risk of relapse.

EXOSOME-BASED LIQUID BIOPSY
Liquid biopsy, as a minimally invasive and cost effective method for sampling of genetic, proteomic and
metabolic material from different types of cancers, has drawn much attention in recent years . Recently, the
[8]
discovery that exosome-based liquid biopsy may have diagnostic and therapeutic applications has garnered
considerable interest . Exosomes are small membranous cell-derived extracellular vesicles of endocytic origin
[9]
with 50-100 nm in diameter . These nano-vesicles are secreted by most type of cells and can be detected
[10]
and isolated from various body fluids such as serum, urine, plasma, saliva, milk and malignant ascites .
[9]
The exact function of exosomes remains largely unknown. Initially, exosomes were considered to function as
cellular garbage bags for the disposal of excess or non-functional cellular constituents [9,11] . Emerging studies have
revealed that exosomes serve as an intercellular courier of important functional biomolecules including protein,
lipid, DNA, messenger RNA, and microRNA . Exosomes have a unique function in modulating intercellular
[12]
communication among both nearby and distant cells in the body and thereby influencing both pathological
and physiological processes. Exosomes interact with their target cells by fusion of membranes and transfer their
content to regulate cellular activities in target cells . Additionally, proteins on the surface of exosomes have
[13]
been known to interact with cell surface receptors on target cells to mediate intracellular signalling .
[13]
In cancers, the production and composition of exosomes are markedly altered. For instance, it is estimated
that approximately 2000 trillion exosomes are contained in normal human blood and the number of
exosomes increase to approximately 4000 trillion in blood of cancer patients [9,14] . The underlying cause
for enhanced levels of exosome production remains unclear. Cancer cell-derived exosomes function in an
autocrine or paracrine manner to modulate the tumour microenvironment . Moreover, the cargo shuttled
[15]
by tumour-derived exosomes determines their effect on target cells, and the exosomes play important roles
in their ability to influence tumour growth and progression. The role of exosomes in the areas of diagnosis,
prognosis and treatment of tumours have been intensively investigated in many cancers, including HCC [13,16] .
Tumour cell-derived exosomes were shown to carry and transfer oncogenes, pathogens and microRNAs .
[17]
Understanding the role of exosomes and their relevance to HCC offers the potential for new biomarkers for
diagnosis and new druggable targets for treatment.

BENEFITS OF EXOSOME-BASED LIQUID BIOPSIES
Exosome-based liquid biopsies have several advantages over traditional biopsies. First, due to its minimally
invasive nature, multiple samples of exosomes can be collected at different time points during treatment.
Whereas, the deeply located tumours are often not accessible to be monitored during treatment and
obtaining multiple tumour biopsies is difficult in clinical settings . Second, similar to cells, the cargo
[18]
of exosomes reflect the metabolic state of cells they originate from, in real time. Exosomes also express
specific markers seen in their cells of origin, making it easier to track the origin of exosomes . Third, they
[9]