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Page 6 of 17 Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60

Liquid biopsy

Metastasis
taMPs
RBC

ctDNA

miRNAs
CTCs

incRNAs

HCC

Figure 1. Liquid biopsy of hepatocelular carcinoma (HCC): circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), epigenetic
non-coding RNA (miRNAS and lncRNA) and tumor-associated circulating microparticles (taMPs)

decision-making during HCC treatment, including the follow-up period; risk assessment, early cancer
detection, treatment response or even prognostic outcome [53-56] .

CTCs
CTCs are spread by tumor malignant cells into peripheral blood in order to reach distal organs and
eventually develop metastatic carcinoma . Several studies have analysed the role of CTCs as a marker to
[54]
predict survival, recurrence or treatment response in different kinds of tumors [53,57,58] .

The presence of CTCs was reported for the first time in 1869 into the blood of a man with metastatic
[59]
cancer . However, there are some limitations about the use of CTCs due to the incapacity in detecting these
cells during the earlier stages of the disease (cells are proportional to tumor volume or aggressive biology
behaviour; the larger the tumor, the higher the CTCs-positive rate in the peripheral blood). Unfortunately
the frequency of finding CTC in blood is 1 to 10 in a background of millions of blood cells in patients with
metastatic disease . In the last years, the major challenge for CTCs researchers has been to improve the
[60]
sensitivity and specificity of CTCs purification in order to perform the molecular characterization of CTCs
to ease the development of “accurate medicine”; a cancer management program.

The clinical relevance of CTCs detection in HCC patients has been deeply studied while CTCs isolation
and enrichment technologies have emerged. The physical methods are based on the physical properties of
[61]
CTCs such as size, density, migratory capacity and electric charge . The biological methods are focused
on antigen-antibody binding against tumor specific biomarkers such as epithelial cell adhesion molecule
(EpCAM), CD133, CD90 and human epidermal growth factor receptor2 (Her2) among others [62,63] . EpCAM
is the most common antigen used for the CTCs isolation; it is the only one clinically validated and approved
by the FDA. However, its use has been controversial due to the epithelial-mesenchymal transition (EMT)
process that is characterized by the decreasing of epithelial markers expression and the acquisition of
mesenchymal profile . EpCAM mRNA+ CTCs enables to differentiate between HCC patients (advance
[64]
and non-advance stage) and non-HCC with 42.6% sensitivity and 97% of specificity (AUC: 0.697). When
combined with AFP level, the diagnostic value of CTCs was significantly improved and the AUC was 0.857
[65]
with a sensitivity of 73.0% and specificity of 93.4% .