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Page 4 of 18 Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13

most widely used CSC markers including CD133, CD44, CK19, CD90, EpCAM, and ALDH are not specific
to LCSCs. CD133+/ALDH+ cells showed to possess stronger tumorigenicity than their CD133-/ALDH- or
CD133-/ALDH+ counterparts . We also found and confirmed that CD133+/ALDH+ cells possess stronger
[30]
[25]
tumorigenicity than their CD133-/ALDH- and CD133-/ALDH+ counterparts both in vivo and in vitro.
Furthermore, we established a hierarchical organization in HCC to demonstrate HCC tumorigenicity from
the highest to the lowest: CD133+/ALDH+ > CD133+/ALDH- > CD133-/ALDH-. Zhao et al. reported that
[11]
some subpopulations of liver cancer cells, including CD133+/1B50-1+, CD13+/1B50-1+ and EpCAM+/1B50-1+
cells, exhibited high tumorigenicity. CD133+/EpCAM+ cells displayed the highest tumor-initiating activity,
compared to CD133+/EpCAM- and CD133-/EpCAM+ cells . Elevated CD133 expression is associated
[52]
with tumor differentiation grades, disease stages and alpha-fetoprotein (AFP) levels. Furthermore, a higher
CD133 expression level indicates higher recurrence rates as well as poorer overall survival [36,53-57] . Recently,
Chen et al. reported that a long noncoding RNA termed LncSox4, is upregulated in CD133 and EPCAM
[58]
high-expressed HCC tissues, modulating the self-renewal of liver tumor-initiating cells via Stat3-mediated
Sox4 expression.

When CD133 as a target was concerned, Sasaki et al. developed a DC-based vaccine inhibited the
[54]
tumorigenicity of CD133+ HCC cells subcutaneously injected into nude mice. Our previous study
demonstrated that AKT1 inhibitor can significantly reduce the expression of the survival proteins that
was primarily expressed endogenously in CD133+ HCC cells . Smith et al. developed an anti-CD133
[59]
[30]
antibody-drug conjugate that could inhibit growth of CD133+ HCC cells. Lang et al. prepared a 131I-
[60]
CD133 monoclonal antibody (mAb) with specific selectivity that could lead to clinical significance in liver
cancer treatment. Huang et al. . developed an bispecific antibody (BsAb) of anti-CD3/anti-CD133 and
[61]
coagulate it to the cytokine-induced killer (CIK) cells to effectively target and kill CD133+ cells.

CD44
CD44, firstly was recognized as a lymphocyte homing receptor , can be broadly detected in multiple tissues
[62]
including embryonic , hematopoietic , mesenchymal , and cancer stem cells [66-69] . In humans, CD44
[63]
[65]
[64]
gene comprises 20 exons and 19 introns and undergoes complicated alternative splicing to generate CD44
standard form (CD44s) [70-72] and CD44 variant splice isoforms . CD44 is involved in the interaction between
[73]
cells and extracellular matrix .
[74]
Williams et al. emphasized on the behavior of CD44-regulating stem cell, including cell differentiation
[75]
and self-renewal and cell-matrix interactions during tumor progression and migration. Isolated CD44s+
cells can effectively form colonies and possess hepatic markers . In HCC, CD44s expression is involved to
[76]
modulation of the mesenchymal phenotype mediated by TGF-beta and its expression level is an unfavorable
prognosis factor . Proliferation of CD44+ cells and its tumorigenesis can be stimulated by IL6 produced
[77]
by tumor-associated macrophages (TAMs) . CD44 expression is known to be related to invasive and
[78]
metastatic behavior of liver cancer . For instance, FAM83D promotes HCC recurrence by increasing CD44
[79]
expression and modulating CD44+ CSCs malignancy . Coexpression of CD44 with other markers such as
[80]
CD133 and CD90 help well identify LCSC phenotypes. CD133+/CD44+ subpopulation is associated with the
metastatic capability in the xenotransplantation assay in nude mice . CD133+/CD44+ HCC cells exhibits
[36]
elevated expression of many CSC-related genes and are more chemotherapy-resistant owing to the increased
expression of transporters that belong to ATP-binding cassette superfamily . Most of CD90+ cells coexpress
[79]
CD44 and these CD90+/CD44+ cells exhibit an aggressive behavior than the CD90+/CD44- counterpart and
easily develop metastases in the nude mice lung . Yang et al. found that administration of anti-CD44
[4]
[4]
antibody was able to induce apoptosis of the CD90+ and CD90- cells in a dose-dependent manner, and
prevented CD90+/CD44+ CSC-derived tumor both locally generated and distantly metastasized .
[4]