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Correnti et al. Hepatoma Res 2018;4:69 I http://dx.doi.org/10.20517/2394-5079.2018.96 Page 5 of 15

Phosphatidyl inositol 3-kinase/AKT signaling
AKT plays a critical role in many human cancers, including HCC and CCA [3,97] . AKT signaling can be
triggered downstream of tyrosine kinase receptors activation, phosphatidyl inositol 3-kinase (PI3K)
[3]
constitutive activation or loss of phosphatase and tensin homolog (PTEN) . PTEN deletion results in the
proliferation of a CD133+ population [71,98] . PI3K signaling promotes stem-like properties of HCC cells and
it is implicated in HCC chemo- and radio-resistance as well as in epithelial-to-mesenchymal transition
(EMT) and metastasis [99-104] . Notably, the co-activation of AKT and neuroblastoma rat sarcoma viral
oncogene homolog (N-RAS) oncogenes leads to development of cHCC-CCA-like liver tumors, through the
[42]
expansion of HPCs or malignant conversion of hepatocyte into progenitor-like cells .

Mitogen-activated protein kinase/extracellular signal-regulated kinases signaling pathway
The mitogen-activated protein kinase (MAPK) cascade regulates many important cell function, such
[71]
as proliferation, invasion and survival and is critical for HPCs proliferation . Gain-of-function
mutations of KRAS are some of the most frequent mutations observed in iCCA, defining a class of
patients characterized by poor outcome and enriched in CCA stem like-cells and tumor recurrence
predicting signatures. Moreover, these mutations are also detected in patients with primary sclerosing
cholangitis, suggesting that this could be an early event that contributes to the malignant transformation
[36]
of cholangiocytes . It is known that the MAPK pathway is directly associated with HCC cell growth and
tumor-initiating capability [105-107] . Moreover, the long non-coding RNA H19 is highly expressed in HCC
cells, where it activates the MAPK/extracellular signal-regulated kinases signaling pathway, regulating
[108]
oxidative stress and chemotherapy resistance of CD133+ HCC CSC .

Transforming growth factor-β signaling
The transforming growth factor-β (TGF-β) pathway plays a key role in self-renewal and maintenance of
an undifferentiated stem cell state. Its disruption is implicated in CCA development through impairment
[98]
of stem cell differentiation and deregulated proliferation of HPCs . Nonetheless, the role of TGF-β
in PLC development is still controversial. Indeed, TGF-β acts as a tumor suppressor early in tumor
initiation, whereas at late stages it promotes tumor growth, metastasis and EMT. It has been demonstrated
that TGF-β1/Snail activation induces EMT in CCA both in vitro and in vivo, and this is associated with
a higher CCA aggressiveness [109] . Moreover, TGF-β is upregulated in 40% of HCCs [69,81,89] , and it may
promote HCC progression via regulatory T cells recruitment and subsequent creation of a tumor suitable
microenvironment [110,111] .

Janus kinase/signal transducers and activators of transcription signaling
Several lines of evidences highlight the central role of interleukin (IL)-6/signal transducers and activators
of transcription 3 (STAT3) signaling in CCA. Binding of IL-6 to the gp130 receptor leads to Janus kinases
(JAKs) (JAK1, JAK2 and TYK2) and STAT3 activation, inducing the transcription of target genes essential
for cell growth, differentiation and proliferation (reviewed in [34,112] ). STAT3 signaling is also involved
in maintenance of CSC population [113-115] and EMT-triggering in diverse tumors, including PLC [116,117] .
Increased IL-6 expression has been reported to drive CSCs expansion through STAT3 activation in
[118]
HCC . Moreover, a recent study has demonstrated that EMT+ metastatic CSCs can be generated in a
+/-
β2SP mouse model of HCC, mainly due to overexpression of IL-6 in addition to the partial disruption of
[119]
TGF-β signaling .
KEY FEATURES OF LIVER CSCS
Drug-resistance
A fundamental aspect contributing to poor PLC survival rate is the unresponsiveness to conventional
therapies [11,12] . Currently, effective treatment is limited to surgical resection for both HCC and CCA, as
well as liver transplantation for HCC. Unfortunately, 80% of HCC patients are diagnosed at an advanced
tumor stage, which is not amenable to curative treatment [8-10] . Although other treatment procedures (e.g.,