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Page 2 of 15 Correnti et al. Hepatoma Res 2018;4:69 I http://dx.doi.org/10.20517/2394-5079.2018.96

[3-5]
second most common form and accounts for about 5% of all PLCs . HCC causes over 600,000 deaths
worldwide annually, and its incidence and mortality are increasing at a fast rate [6-10] . On the other hand,
CCA is characterized by a very poor prognosis, with a 5-years survival lower than 20%, and its incidence
and worldwide mortality are also increasing [5,11-13] . The high mortality rate of CCA may depend on its non-
specific or silent clinical features and the lack of specific markers that make it difficult to diagnose [14-16] .

Many studies carried out in these last years have attempted to define which type of epithelial cell
[hepatocytes, cholangiocytes, hepatic progenitor cells (HPCs) or all three] should be considered as the PLC
[17]
cell of origin . For a long time, HCC and CCA have been commonly accepted to derive from hepatocytes
and cholangiocytes, respectively. Since mature hepatocytes and cholangiocytes have an enormous self-
renewal capacity and longevity, they meet the requirements to be targets for oncogenesis [17-23] . Detailed
analyses of a wide range of PLC tumor types have reported that a rare form of combined HCC-CCA
(cHCC-CCA) has intermediate characteristics between HCC and intrahepatic CCA (iCCA), suggesting
that they could share the same stem/progenitor cell origin [18-24] . In this regard, since most PLCs arise
on the background of chronic liver disease in the presence of an extensive activation of the HPC
compartment (the so-called ductular reaction), several studies suggested that PLCs can be derived
[25]
from HPCs rather than from mature cell types . HPCs situated in the canal of Hering physiologically
act as a reserve cell compartment activated in case of liver damage or when mature hepatocytes and/
or cholangiocytes replication is compromised. These cells are bipotential, and may differentiate into
either hepatocytes or cholangiocytes [26-28] . During the differentiation in malignant cells, bipotential
HPCs undergo maturation arrest and give rise to a spectrum of tumor phenotypes with both admixed
hepatocellular and cholangiocellular features, such as cholangiolocellular carcinoma and cHCC-CCA [29-31] .
Additionally, a new subtype of CCA-like HCC (CLHCC) has been discovered and characterized as HCC
[32]
expressing CCA-like traits . CLHCC co-express embryonic stem cell (ESC) traits and hepatoblast-
like genomic signatures, suggesting a HPC origin. These lines of evidence provided important insight
into the heterogeneous progression of PLCs, which imply a common evolutionary origin from cells at
different developmental stages [31-33] . The hypothesis of a progenitor cell origin has been supported by new
advancement in genome wide analysis. Indeed, it has been suggested that iCCA and HCC are closely
related at molecular level [19,29,34,35] , since both tumor types share common copy number variations [11,36] .

Such phenotypic variability and presence of progenitor cell features in PLC can be explained in two ways:
either the cell of origin is a progenitor cell with acquired genetic alterations or, alternatively, mature
tumor cells de-differentiate acquiring progenitor cell features during carcinogenesis (de-differentiation
theory [37-40] ). Interestingly, new findings provide direct evidence that any cell in the hepatic lineage can
[41]
be the cell of origin of PLC . In this regard, it has been recently suggested the development of iCCA by
lineage conversion of malignant hepatocytes, through a co-activation of both Notch and protein kinase B
(AKT) signaling, contributes to the acquisition of stem/progenitor cell features [42,43] . In spite of the marked
plasticity in the underlying cells of origin, current evidence suggests that most PLCs are derived from
[40]
undifferentiated cells with stem-like capabilities .
UNDERSTANDING THE CONCEPT OF CANCER STEM CELL
Extensive clinical and pathobiological heterogeneity at the level of cellular morphologies, genetic
fingerprints and responses to therapies is a cardinal hallmark of cancer, including PLC. Such tumor
complexity may reflect the presence of different cell subtypes with distinct self-renewal and differentiation
potentials [40,44-46] . The traditional view of cancer development is based on a stochastic model, which states
that every malignant cell may undergo genetic and/or epigenetic alterations and clonally expand to
initiate tumor growth. Thus, every cell within the tumor may be equally responsible for tumor initiation
and progression [47-51] . Unlike the stochastic model, the hierchical or cancer stem cell (CSC) model may
explain intra-tumor heterogeneity representing tumor as a hierchically organized tissue with CSCs at
the apex in the pyramid and more committed and differentiated tumor cell types progressively down [47-50] .