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Page 6 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

evidence supports ABCG2 as playing a vital role in enhancing stem cell proliferation and in the case of
esophageal squamous carcinoma has been shown to be required for the maintenance of the stem cell
phenotype [39,40] .

Therefore, ABCG2 has applications not only in the identification of the CSCs, but also for allowing the
possibility of blocking its function as one way for improving selective drug targeting of tumors and their
[41]
CSC population during the course of anticancer chemotherapy . Despite the supportive evidence that
ABCG2 is a stem cell marker, there are limitations since the exact role of the ABCG2 signalling pathway and
its regulation is not well understood [42,43] . Although the molecular mechanisms regulating ABCG2 expression
are not clearly understood, it is likely that the MYC oncogene plays an important role in promoting its
[44]
expression in some cancers .
In studies of “SP” cells isolated from human colorectal cancer cell lines, it was shown that expression of ABC
transporter genes, such as ABCB1 and ABCG2 was significantly higher, linked with greater resistance to
5-FU and irinotecan, and higher activation of the WNT signalling pathway, than for the non-SP cells . In
[45]
addition, silencing b-catenin expression to inhibit WNT decreased significantly more SP cells than non-SP
cells, decreased transcription of the ABC transporter genes and the silenced cells became relatively sensitive
to paclitaxel and irinotecan. Hence, these results indicate that ABC expression is regulated by WNT
signalling. EMT induces a switch in WNT signalling from a b-catenin/E-cadherin/Sox15 transcription
factor complex to the b-catenin/Twist1/TCF-4 complex, the latter of which then binds to promoters
[46]
of the CSC-related genes . In this study, it was shown that Twist1 binding to b-catenin enhanced the
transcriptional activity of the b-catenin/TCF-4 complex, including by binding to the proximal promoter
[46]
region of the ABCG2 gene to promote ABCG2 expression as one CSC marker .
Zhang et al. showed that the sensitivity of hepatocarcinoma cells to the chemotherapeutic drugs,
[35]
doxorubicin or 5-fluorouracil inversely correlated with surface levels of the ABCG2 marker. The levels of
ABCG2 expressed on cancer cells including colon cancer lines also closely correlated with tumorigenicity,
drug resistance, proliferation and metastatic ability and therefore, the ABC transporters could be considered
as critical and universal biomarkers for all CSCs [34,35,47,48] . The results above of WNT signalling correlating
with ABCG2 expression levels also support strategies aimed at inhibiting the WNT signalling pathway as a
means for targeting chemotherapy-resistant colon cancer cells, including the CSCs.

CD133
CD133 (a.k.a. prominin-1) has been widely touted to be a CSC marker and was originally recognized as
a stem cell marker found on rat neuroepithelial stem cells . CD133 and its role as a CSC biomarker has
[49]
[50]
recently been reviewed . As a common biomarker, CD133 has been used for identifying many different
types of CSCs, including those originating from gliomas , colorectal [10,52,53] , lung , liver , and prostate
[51]
[54]
[38]
[55]
cancer . However, CD133 has been shown to function in regulating glucose uptake for glucosamine
production under conditions of increased glucose and glycolysis and is involved in autophagy [56,57] .
Despite the fact that CD133 can mark the tumor-initiating cell populations in several solid tumors, studies
have shown that it does not play a crucial role in the process of CSC maintenance. Thus, unlike knocking
down CD44 expression which inhibited tumorigenesis of CR-CRC cells, knocking down CD133 gene
[58]
expression had no effect . CD133 expression is also not restricted to the stem cell population because both
the CD133 and CD133 metastatic colon cancer cells were equally capable of initiating tumor production .
+
[59]
-
Hence, CD133 expression is more a reflection of the level of glucose availability and is not necessarily a
specific marker of CSCs.
CD44
CD44 is an extensively glycosylated surface protein as a major component of the extracellular matrix
involved in cell-cell interactions, cell adhesion and migration and is one of the cellular receptors for