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Page 8 of 15 Correnti et al. Hepatoma Res 2018;4:69 I http://dx.doi.org/10.20517/2394-5079.2018.96

Figure 2. Key features of liver cancer stem cells (CSCs). Liver CSCs present some common key functional features. CSCs represent a
peculiar sub-compartment of tumor cells crucially involved in drug resistance. Current therapeutic strategies for the treatment of hepatic
cancer mostly focus on the inhibition of tumor growth, resulting in the death of only bulk tumor cells. CSCs are able to survive thanks to
intrinsic and extrinsic mechanisms of chemo-resistance and subsequently they can give rise to primary liver cancer recurrence. Moreover,
CSCs are the only cells endowed with metastatic potential. While mature tumor cells mostly die through natural apoptosis into blood
circulation, CSCs, however, have a significantly higher viability, enhanced homing ability into the bloodstream as circulating CSCs as
well as higher distant metastasis initiation capability. Next, CSCs are characterized by metabolic changes, but, no consensus has been
reached on the metabolic features of CSCs, which are very plastic and so able to modify their metabolic features according to specific
needs. Then, CSCs can exhibit enhanced glycolytic activity as well as increased mitochondrial oxidative phosphorylation (OXPHOS) with
subsequent increased fatty acid oxidation, depending on tumor context. All these features make CSCs particularly hard to eradicate. FAO:
fatty acid oxidation

are increased in CD133+ cells, and this is directly correlated with SIRT1-dependent enhanced FAO [144] .
In HCC, genome-wide transcriptional profiling and Ingenuity pathway analysis have suggested NANOG
to be the connecting point between FAO and stem-like features, because of its simultaneous OXPHOS
[145]
repression and FAO activation actions . Moreover, it has been observed that stearoyl-CoA desaturase 1
(SCD1), a central enzyme involved in the conversion of saturated fatty acids into monounsaturated fatty
[146]
acids (MUFAs), regulates liver CSCs . In addition, enhanced activation of SCD1 and the consequent
[141]
production of MUFAs appear to be a potential hallmark of CSCs .
All these findings prompt metabolic plasticity as a central force that enables CSCs to modify their
replicative capabilities according to specific needs [Figure 2]. Further, emerging evidence suggests that
[147]
CSCs may adopt specific metabolic phenotypes based on their location within tumor mass .

CONCLUSIONS AND CLINICAL IMPLICATIONS
Unresponsiveness to current conventional therapies remains one of the major challenges in PLC. Current
therapeutic strategies for the treatment of hepatic cancer mostly focus on the inhibition of tumor growth,
with unsatisfactory results. Future treatments are likely to target CSCs and their specialized niche. In
this view, it is imperative to decipher the molecular mechanism behind chemoresistance of PLC cells and
especially of CSCs, with the objective to develop novel therapeutic strategies targeting features, markers
or signaling pathways essentials for CSC biology.