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factors for HCC include cirrhosis, hepatocarcinogenic like control normal hepatic regeneration via DNA synthesis
aflatoxins and nitrosamines, dietary and environmental stimulation. TGF-β and activin serve as negative feedback
carcinogens by generation of reactive oxygen species mechanisms and regulate the end point of the hepatocyte
(ROS) and infections like hepatitis B and C viruses. [2] proliferation. This termination is regulated by the ratio of
liver to body mass thus providing a check on the extent of
The current management of liver tumors is not satisfactory. liver regeneration. [14]
Chemotherapy, surgery, and radiofrequency ablation are
all directed at reducing the tumor bulk. However, in the Liver stem cells are proposed to be from dual origins,
majority of cases, tumor recurrence and relapse occurs on intrahepatic with short-term proliferative capacity present
completion of therapy. Also, liver cancer is diagnosed at within the canals of Herring and interlobular bile ducts and
an advanced stage quite frequently; hence the available extrahepatic derived from bone marrow and peripheral
chemotherapy regimens fail to offer a complete cure. Even blood cells with long-term proliferation capacity. [15]
if chemotherapy has been instituted timely, the available
chemotherapeutic agents are reported to show severe MOLECULAR SIGNALING PATHWAYS IN LIVER
adverse effects. Angiogenesis plays a significant role in CANCER
human HCC tumor progression and recent studies are
focussing on anti-angiogenic agents targeting specific Liver cancer stem cells have many signals to maintain
tumor vasculature. [3] self-renewal and pluripotency including EpCAM, Wnt/β-
catenin pathway, Sonic Hedgehog pathway, and Notch
In this regard, discovery of natural phytocompounds pathway, which play a decisive role in the regulation
having anti-tumor and anti-angiogenic activities could have and maintenance of stemness and in tumor formation.
greater clinical significance as they do not affect physiology Tumorigenesis results from uncontrolled activation of
and survival of normal cells. Many phytochemicals have these pathways. Wnt pathway proteins regulate the
proven anti-tumor action including catechins, quercetin cellular fate and self-renewal of stem cells. The Notch
[16]
in apples and onions, resveratorl in grapes, red wine, pathway is involved in cellular differentiation, fate of the
peanuts, and ellagic acid in pomegranates. [4-7] This review cell, cellular proliferation, apoptosis, and cell adhesion.
describes firstly the molecular pathology of liver cancers Notch signaling in the liver is involved in cholangiocyte
and then summaries the evidence based literature that differentiation. [17]
describes the various proven mechanism demonstrating
the anti-tumor potential of curcumin in turmeric (Curcuma HEPATOCELLULAR CARCINOMA
longa) and thus exploring its role as an adjuvant therapeutic
remedy for liver cancer. EpCAM signaling pathway
EpCAM consists of a large extracellular, a single
CURCUMIN transmembrane and a short intracellular domain. There
is a cross-talk between EpCAM signaling and the Wnt
Curcumin is the active phytoconstituent of turmeric. It pathway. [18,19]
has been widely used as a therapeutic medicine in Indian
traditional medicine. Of late, scientists all over the world Wnt/β-catenin signaling pathway
have recognized its therapeutic potential as an anti- The Wnt/β-catenin pathway is essential for development,
[20]
inflammatory, anti-oxidant and anti-cancer agent. [8-11] growth, survival, regeneration, and self-renewal.
Curcumin inhibits lipid peroxidation and maintains the Disruption of Wnt/β-catenin signaling by mutational and
normal concentration of intracellular antioxidant enzymes non-mutational events is associated with many cancers,
like catalase, glutathione peroxidase and superoxide including HCC. Disrupted Wnt/β-catenin signaling
dismutase and scavenges reactive oxygen species pathway has been reported in around one third of all
effectively. [12,13] HCCs. However, the point at which cross-talk occurs
[21]
in the signaling cascades of Wnt/Frizzled and EpCAM
TUMORIGENESIS AND MOLECULAR BIOLOGY OF remains unknown.
LIVER CANCER
SALL4 signaling pathway
Tumorigenesis of liver cancer is a complex process. The As an oncofetal gene, SALL4 is expressed at high levels in
recognition of tumor stem cells and their molecular fetal-liver progenitor cells but not in adult hepatocytes,
signaling has opened new pathways for therapeutic and it has an important role in hepatic cell lineage
strategies. The liver has great potential to regenerate after commitment. [22,23]
the loss of hepatic tissue which depends on proliferation
of existing mature hepatocytes. TGF-β family
The TGF-β family controls cellular differentiation and
Growth factors like hepatocyte growth factor, epidermal proliferation in both cancer stem cells and cancer cells.
growth factor and transforming growth factor (TGF)-alpha Impaired TGF-β signaling through the activation of

Hepatoma Research | Volume 2 | March 9, 2016 63