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Page 2 of 18 Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13

INTRODUCTION
Liver cancer is the seventh most frequently diagnosed cancer and the third death causing of cancer around
[1]
the world, which has 841,080 newly diagnosed cases and caused 781,631 deaths in 2018 . Hepatocellular
carcinoma (HCC) comprises 75%-85% of the primary liver cancer cases and intrahepatic cholangiocarcinoma
[1]
and other rare types comprise 15%-25% . Chronic hepatitis B virus infection, hepatitis C virus infection,
steatohepatitis and cirrhosis are the most prevalent precursors to HCC. Despite of the recent advances in
liver cancer therapies, the current treatment cannot effectively prevent tumor recurrence and metastasis due
to the existence of (liver cancer stem cells) LCSCs. The concept of cancer stem cells (CSCs) is raised from
clinical and experimental observations that there exists a subpopulation of cancer cells that possess stem
cell-like characteristics including self-renewal and differentiation that eventually lead to cancer relapse and
resistance. LCSCs have been reported in varied types of HCC and are deemed to be one of the major causes
of HCC recurrence, metastasis, chemoresistance and radioresistance.

Conventional therapies against non-stem liver cancer cells such as chemotherapy and radiotherapy, have
multiple limitations that result in cancer recurrence and metastasis due to acquired resistance. The survival
LCSCs can re-initiate tumor development and invasion [Figure 1]. Hence, in order to develop feasible
therapies that can prevent tumor recurrence and metastasis, it is important to specifically identify, target and
eliminate LCSCs. Recent advances in LCSC surface markers and understanding of cellular features related
to LCSC phenotypes greatly improve the efficacy of treatments that target LCSCs. Targeting the LCSCs with
high expression of certain stemness surface markers, can manipulate the abilities of LCSCs in proliferation,
growth, maintenance, differentiation, resistance and apoptosis via cellular signaling pathways so that tumor
regeneration can be impeded.

In order to develop patient-specific therapies that target LCSCs, multiple stemness surface markers have
[2]
[5]
[6]
[3]
been identified consisting CD133 , CD44 , CD90 , epithelial cell adhesion molecule (EpCAM) , CD47 ,
[4]
CD34 , C-kit , CD13 , CD24 , calcium channel α2δ 1 isoform5 , oval cell marker OV6 , DLK1 ,
[7]
[12]
[13]
[11]
[10]
[9]
[8]
[14]
K19 , and Lgr5+ [Table 1]. The integrated therapy using conventional anti-carcinogenic inhibitors
[15]
such as sorafenib with LCSCs-targeting drugs, may provide an effective therapeutic strategy for complete
elimination of liver cancer.
CD133
CD133, also referred to as PROM1, is a member of prominin family that has a structure of five transmembrane
single-chain glycoprotein with a molecular weight of 115 ~ 120 kDa, including an extracellular N-terminus,
two large extracellular loops, two small intracellular loops and an intracellular C-terminus [16-19] . CD133 was
originally identified as a surface marker of hematopoietic stem cells . In solids tumor, CD133 was firstly
[16]
identified and further isolated in brain tumors . Later, the role of CD133 as a surface marker of CSC is
[20]
been reported in a wide variety of tumor tissues such as lung cancer , stomach carcinoma , pancreatic
[22]
[21]
cancer , colon cancer , and liver cancer that was identified by our team [25-27] .
[24]
[23]
In 2006, Suetsugu et al. reported that CD133+ liver cancer cells, sorted from the Huh7 cell line, exhibited
[28]
a more potent capability of proliferation and metastasis compared to the CD133- counterparts. Our
previous study indicated that CD133+ cells also processed a stronger cology-forming characteristic, greater
tumorigenicity and potential to differentiate into angiomyogenic-like lineages . We also further characterized
[2]
the liver CD133+ CSCs, revealing that CD133+ cells were endowed with high in vivo tumorigenicity and
the capability to form spheroids with an upregulated expression of stemness-associated genes in vitro [29-31] .
Liu et al. reported that CD133 was crucial to monitor the migratory capability of LCSCs, tumor-initiating
[32]
properties, and the epithelial-mesenchymal transition (EMT) process. Tang et al. demonstrated that CD133+
[33]
[35]
liver tumor-initiating cells (TICs) had angiogenesis ability. In addition, Li et al. and other researchers also
[34]
found that CD133+ HCC cells could exploit autophagy to maintain their survival. Liver CD133+ CSCs are