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Page 10 of 18 Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13

NCCN guidelines for hepatobiliary cancers, version 4.2018), several oral targeted drugs have been approved,
including sorafenib, lenvatinib, regorafenib, showed a median overall survival of 10.7 to 13.6 months [185-187] .
Immunotherapy has also been considered as one of the promising treatments and is being actively studied
and optimized in liver cancer progression and metastasis . The most ex vivo investigated and clinically
[188]
relevant check-point proteins are CTLA-4, PD-1, and PD-L1. Nivolumab and pembrolizumb, both as PD-1
antibodies with similar efficacy, are now approved to treat liver cancer clinically. Nivolumab showed an
objective response of 20%, contained 1% complete response and 18% partial response, and stable disease is
45% , when pembrolizumb is concerned, the objective response is 17%, and the complete responses, partial
[189]
response, and stable disease were 1%, 16% and 44% respectively . The development of new drugs enable
[190]
the improvement of object responses and survival of advanced liver cancer, what’s deserved notification is
that drugs such as sorafenib, lenvatinib, regorafenib, nivolumab and pembrolizumb now available in clinic
can obtained about 1% clinical complete response in small number of patients, revealing the pathways these
drugs targeted may have the potential to diminished almost the whole tumor including the LCSC, and
further exploration of the underlying mechanism of cancer development and progression is promising.

Alternative therapies including induction of LCSC differentiation and apoptosis are also promising.
Conventional chemotherapy and radiotherapy have been proven to successfully eradicate terminally
differentiated cancer cells but fail to influence CSCs [191,192] . Therapies that induce LCSC differentiation can be
combined with those conventional therapies to efficiently diminish LCSC subpopulation and impede cancer
development since the differentiation process obtains higher priority than cancer self-renewal process. There
are intensive studies developing and optimizing the differentiation-inducing agents including retinoic acid,
histone deacetylase inhibitors, tyrosine-kinase, Hippo/YAP signaling pathway inhibitors [192-195] . Apoptosis is
also a vital cellular mechanism that regulates cell death through a complicated signaling network. LCSCs can
escape from apoptosis process, therefore they possess unlimited and uncontrollable self-renewal ability to
initiate cancer development and invasion. Induction of apoptotic mechanism in LCSCs by using microRNA
hold great promise in cancer treatment so that many studies have been focused on developing therapies to
activate apoptotic pathways in LCSCs .
[196]

These inducing therapies would be feasible and efficient if LCSCs could be specifically identified according to
the expression profile of varied LCSC surface markers. However, there is no LCSC surface marker has been
identified and proven to have the ability to represent the entire subpopulation of LCSCs, thereby the inducing
therapies remain challenging so far. It leads us to consider that whether or not the potential combination of
varied LCSC surface markers can improve the specificity in identification of LCSCs.

SUMMARY
The above-mentioned discussion offers a promising insight of how LCSCs can be employed in clinical
diagnosis and treatment for liver cancer development, progression, metastasis and resistance [Figure 2].
During the last decades, the compelling knowledge about CSCs has enabled rapid advances of drugs targeting
CSCs and gradually emerged as an indispensable class of therapies. Numerous agents with the capabilities
to inhibit CSC-associated signaling pathways, including Notch pathway, Hedgehog pathway and WNT
pathway, have been approved for clinical use. The recent development of culture condition allows CSCs
to undergo long-term proliferation in spheroids and organoids, thus offer researchers with an innovative
platform for identifying new CSC markers with high specificity and efficacy. Moreover, because organoids
are directly derived from primary tumor tissues, the organoid technique provides a unique perspective to
researchers so that we can comprehensively investigate the heterogeneous functions of CSCs in recurrence,
metastasis, chemoresistance and radioresistance.

From a broader perspective, there is no doubt that drugs targeting CSC should be considered as a promising
clinical strategy for therapeutic intervention, although the rate of treatment failure that aims to effectively