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Page 12 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

CD15 (stage-specific embryonic antigen 1)
Stage-specific embryonic antigen 1 (SSEA1; also called CD15 or non-sialylated Lewis X antigen) refers to a
carbohydrate based antigenic epitope (3-fucosyl-N-acetyl-lactosamine) synthesized by fucosyltransferases
(FUT4, FUT9) and is linked with cell adhesion, differentiation and migration. This marker is associated with
the proteoglycan, phosphacan (a.k.a. protein tyrosine phosphatase receptor-Z1; RPTPZ1; PTPRZ1) which
regulates the proliferation, self-renewal and differentiation of stem cells [154] . RPTPZ1 is a receptor for the
extracellular matrix protein, tenascin C recently linked with EMT, metastasis, recurrence and poor survival
of CRC patients [155] .

CD15/SSEA1 is expressed by murine embryonal stem cells, murine embryonic carcinoma cells, as
well as human and murine germ cells [156] . SSEA1 has been widely used as a positive surface marker for
[39]
undifferentiated normal stem cells from mice but not for human stem cells . Thus, upon differentiation
of the murine embryonal stem cells or embryonal carcinoma cells, expression of SSEA1 is down-regulated,
whereas during human embryonal stem or carcinoma cell differentiation, SSEA1 expression is increased.
The SSEA-1 marker is commonly used for identifying stem cells because it can be readily detected using the
monoclonal antibody, MC-480, as a cell surface antigen involved in cell differentiation. This monoclonal
antibody has also been commonly used as a standard reagent for detecting embryonic stem cells [157] .

SSEA-1/CD15/FUT4 was found commonly overexpressed on metastatic CRC patients (43%) and was
+
+
associated with lower levels of intratumoral CD3 and CD8 T cells, as well as poorer patient outcomes
in terms of responses to treatment or progression-free survival (PFS) than those CRCs that were CD15/
FUT4-low or negative [158] . Studies of brain development have shown that expression of CD15/SSEA1 is
[159]
predominantly associated with O-mannose-linked glycans of the phosphacan/RPTPZ1 and high levels
of RPTPZ1 expression have also been reported present in human CRC samples [160] . Hence, although SSEA-1
may be a putative CSC marker in the case of murine CRC, it is likely to show a more widespread expression
on human CRC cells.

COX-2 AND CELECOXIB AS AN APPROVED DRUG FOR COLORECTAL CANCER, ALSO
TARGETS CSCS, INCLUDING CR-CSCS
Celecoxib was approved nearly 20 years ago by the USFDA for the treatment and prevention of some
forms of colorectal cancers, including familial adenomatous polyposis and sporadic colorectal adenoma.
The anticancer effects of celecoxib were claimed due to its potential for inhibiting the enzyme, COX-2 in
the CRC cells [23,161-163] . COX-2 (also known as prostaglandin-endoperoxide synthase 2) uses arachidonic
acid to produce the prostaglandin H2 required to synthesize the prostanoids including thromboxane,
prostaglandins such as PGE2 and prostacyclin. COX-2 is overexpressed in many cancer cell types, including
CRC [164] when compared to levels in the corresponding normal cells. Moreover, COX-2 was recently detected
in the CTC populations from CRC patients, where COX-2 expression was associated with those tumor CTCs
positive for vimentin and Twist as two markers detected co-expressed at a higher frequency in patients with
[165]
metastases compared to those without (72.0% vs. 42.8%) .

The role of COX-2/PGE in CRC and relationship to LGR5/WNT activation and survival of CSCs
The tumor cell inhibitory mechanism of celecoxib was proposed to involve counteracting the increased
levels of COX-2 enzymatic function in colorectal cancer cells [Figure 3], thereby causing the suppression of
[166]
cancer cell growth ( , reviewed in [167] ). As outlined above, one of the mechanisms of action by inhibiting
COX-2 likely involves interfering with the WNT/PGE2 signaling pathways that would otherwise promote
greater levels of LGR5 and cancer cell stemness. Among the tumor-sustaining prostaglandins produced by
COX-2, PGE2 is associated with enhancing cancer cell survival, growth, migration, invasion, angiogenesis,
and immunosuppression [168] and can act in an autocrine/paracrine manner to promote tumor growth and
survival [169] [Figure 3]. Inhibiting COX-2 with celecoxib would thereby block the growth stimulating effects