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Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60 Page 5 of 17

[33]
mechanism of the GC33-induced tumor growth inhibition is an antibody-dependent cellular cytotoxicity .
A phase I study have already shown its tolerability at doses of 20 mg/kg/week, with little response [34,35] . In
a randomized placebo-controlled phase II clinical trial conducted subsequently in patients with advanced
[36]
HCC previously treated, codrituzumab showed no clinical benefit in this population .
On the other hand, a GPC3 peptide vaccine that induces peptide-reactive cytotoxic T lymphocytes (CTLs)
has also been tested, with a good response in mice, where it has shown to be able to induce a durable
[37]
regression in GPC3 tumors . It has proven to be adequately tolerated in humans, maintaining radiological
+
stability in most patients. In addition, the overall survival was significantly longer (12.2 months, 95% CI: 6.5-
18.0) in patients with high CTL specific frequencies of GPC3 than in those with low frequencies (8.5 months,
[38]
95% CI: 3.7-13.1; P = 0.033) . These results have been subsequently confirmed, but further studies are needed
[39]
because of the small sample size of these trials .
Therefore, new therapies with GPC3 are being developed as a therapeutic target as well as a diagnostic
marker, and new studies with a larger sample size are necessary. Finally, biomarkers can also be used to
establish new treatment strategies, such as GPC3, but more studies and clinical trials to validate their
response and to improve the prognosis are required.

SERPINB3
SERPINB3 (formerly known as squamous cell carcinoma antigen-1) is a Clade B Serine Protease Inhibitor
physiologically found in the spinous and granular layers of normal squamous epithelium, such as tongue,
[40]
lungs, uterus and others, while become overexpressed by neoplastic cells of these organs . Recent studies
[41]
showed that an aberrant expression of this protein also extends to cancers of other origin such as HCC .
In fact, while it is not detected in normal hepatocytes, its expression progressively increases during the
progression of chronic liver disease and hepatic carcinogenesis.

Furthermore, it was recently confirmed that its expression correlates with that of TGF-B1 and that in fact,
[42]
SERPINB3 contributes to TGFB1 overexpression and release . So, far from its antiprotease activity, and
its biomarker possibilities, SERPINB3 was suggested to be an oncoprotein in as much as it protects the cells
[43]
from apoptosis and induces epithelial-mesenchymal transition, cell invasiveness and proliferation . Lastly,
it has been found that its overexpression induces chronic unfolded protein response and as a consequence,
[44]
activation of NF-kB and production of IL-6 . Besides, a knock-down of SERPINB3 produces an inhibition
[45]
of tumor growth .

In terms of circulating biomarker, it has been described that natural IgMs bind to several tumor antigens
and create immunocomplexes, that in this case, showed a better diagnostic performance that the biomarker
[46]
itself . Accordingly, levels of circulating SCCA-IgM have been recently found to increase over time, being
[47]
predictive of fibrosis progression in patients with chronic hepatitis . Furthermore, it has been demonstrated
that HCV-infected cirrhotic patients with low levels of serum SCCA-IgM have a decreased risk of developing
[48]
HCC . Eventually, Biasiolo et al. reported that SCCA-IgM, instead of AFP, was associated with the
[44]
prediction of HCC-free survival in a prospective cohort .

LIQUID BIOPSY OF HCC
“Liquid biopsies” are based on the analysis of tumor components that are shed into the circulation, such as
tumor-derived extracellular vesicles, circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA)
[Figure 1] [49,50] . Numerous studies have shown the potential utility of circulating cancer byproducts detection
from which we could extract molecular information about primary tumors [51-54] . The liquid biopsy could
be conducted in repeated samples providing accessible, accurate and dynamic information to evaluate the
tumor status. These novel biomarkers are thought to have great potential and could provide individualized