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Page 6 of 16 Cardinale et al. Hepatoma Res 2018;4:20 I http://dx.doi.org/10.20517/2394-5079.2018.46

associated with the development of small bile duct (mixed) type iCCA . Ductular reaction is a marker
[4]
strongly associated with the evolution of chronic liver disease in cirrhosis. The origin of the small bile duct
type iCCA may be associated with the chronic proliferative activation of hepatic stem cells and mature
hepatocytes senescence in chronic liver diseases [12,82] . Since cirrhosis, chronic hepatitis B and C, alcohol
use, diabetes, and obesity are major risk factors for iCCA and HCC , a common pathogenesis of primary
[75]
intrahepatic epithelial cancers has been suggested. The parallel worldwide reduction of mortality of HCC ,
[12]
which is highly correlated to viral infection and cirrhosis, and on the pandemic of metabolic disorders,
suggests that metabolic risk factors are responsible for the rising clinical impact of iCCA. Interestingly
we provided the pathologic basis of this epidemiology phenomenon since we demonstrated DM-induced
proliferation of PBG cells .
[72]

MOLECULAR PROFILING AND THE IDENTIFICATION OF MULTIPLE iCCA SUBSETS
Although there exist enormous geographic and racial differences [3,83] , generally, the prominent genetic
alterations described in CCAs affect TP53 (DNA repair) [84-86] , tyrosine kinase (KRAS, BRAF, SMAD4 and
FGFR2) [8,84-88] , protein tyrosine phosphatase (PTPN3) , deregulated WNT/CTNNB1 and Notch pathways,
[90]
[89]
epigenetic (IDH1 and IDH2) [28,84,88,91,92] , and chromatin-remodeling factors (MLLs, ARID1A, PBRM1 and
BAP1) [84-86,88,91] .

Chronic bile duct inflammation characterizes CCA risk factors [93-95] . Accordingly, it was demonstrated that the
enzyme cyclooxygenase-2 (COX-2) is induced in CCA by both bile acids and oxysterols, the oxidation products
of cholesterol that are increased in the bile during biliary inflammation [96,97] . Inflammatory cytokines may
also upregulate the expression of inducible nitric oxide synthase (iNOS) in CCA. Notably, nitric oxide (NO)
promotes DNA damage directly by inhibiting DNA repair mechanisms, thus promoting carcinogenesis [98,99] .
Moreover, iNOS activation stimulates further the expression of COX-2 . Notably, the tumoral stroma seems
[100]
to have a peculiar role in the amplification of the inflammation. While the tumor epithelium was defined
by deregulation of the HER2 network and frequent over-expression of EGFR, the hepatocyte growth factor
receptor (HGF/MET), pRPS6, and Ki67, the stroma was enriched in inflammatory cytokines .
[101]
In the chronic inflammation milieu of CCA emerging in hepatitis infection , recurrent genetic variants
[88]
in the promoter of the human telomerase reverse transcriptase (TERT) were described . This could be
[88]
correlated with the pivotal role of this “longevity” enzyme in controlling stem cells. These cells are extremely
challenged in these conditions because the senescence of the mature hepatocytes determines the secondary
stem proliferative activation (e.g. ductular reaction) .
[12]
A dissection of the molecular heterogeneity of iCCA, conducted by the evaluation of gene expression profile
(transcriptome), clinic-pathological traits, and patient outcomes in iCCA cases, has allowed the identification
of 2 main biological classes of iCCA. The first inflammation class (38% of IH-CCA), characterized by activation
of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation and; the second
proliferation class (62% of IH-CCA), characterized by activation of oncogenic signaling pathways (i.e. RAS,
MAP-kinase and HGF/MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and
BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC .
[7]

Molecular studies of human iCCA associated with liver flukes demonstrated over-expression of genes involved
in xenobiotic metabolism (UGT2B11, UGT1A10, CHST4, SULT1C1). Whereas non-OV-associated iCCA showed
enhanced expression of genes related to growth factor signaling (TGFBI, PGF, IGFBP1, IGFBP3) [32,102] . Possible
mechanism associated with liver flukes carcinogenesis may emerge from the discovery of the draft genome of
Clonorchis sinensis and transcriptomes of Clonorchis Sinensis and OV [103,104] . For instance, the evaluation of the
putative signature of liver flukes associated CCA could help in screening and surveillance, with the perspective
of an early diagnosis of infestation in subjects . A putative role of liver fluke infestation in modulating
[102]