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Uchihara et al. J Cancer Metastasis Treat 2018;4:9 I http://dx.doi.org/10.20517/2394-4722.2017.81 Page 3 of 8

CD133
One study examined the expression of three putative CSC markers, including ATP-binding cassette sub-
family B member 1, ATP-binding cassette sub-family G member 2, and CD133, in 90 human GC tissue
samples and three human GC cell lines. The authors concluded that the expression levels of these markers
in GC varied with the degree of differentiation, while poorly differentiated GC expressed high levels of these
markers. Furthermore, CD133 expression in GC cells could be divided into two forms: luminal expression in
the gland and cytoplasmic expression. A multivariate analysis revealed that the expression of CD133 in the
cytoplasm was an independent prognostic factor in GC [25,26] .

Other GCSC markers
In addition, aldehyde dehydrogenase 1 (ALDH1) has been identified as a marker of GCSCs. ALDH1+ cells
derived from a diffuse-type GC cell line had a higher tumorigenic capacity in vitro and in vivo compared
with ALDH1- cells and were capable of self-renewal and the generation of heterogeneous cell populations.
Moreover, regenerating islet-derived family member 4 (REG4) was overexpressed in ALDH1+ GCSCs,
and ALDH1 and REG4 expression were down-regulated by transforming growth factor-b (TGF-b), which
correlated with a reduction in the GCSC population and tumorigenicity [27,28] . CD90+ cells, which possessed a
greater ability to initiate tumors in vivo compared with CD90- cells, could re-establish the cellular hierarchy
of tumors from single-cell implantation, which demonstrates their self-renewal properties. In addition,
previous studies on chemo-resistance revealed that ERBB2 was overexpressed in approximately 20%-
25% of the gastric primary tumor models, which correlated with the higher level of CD90 expression in
these tumors [29,30] . Moreover, trastuzumab treatment could decrease the CD90+ population in these tumor
masses and could suppress tumor growth when combined with traditional chemotherapy. Taken together,
[30]
this evidence suggests that CD90 may be another potential candidate marker of GCSCs . The CD71-
fraction of GC cells was enriched after treatment with 5-fluorouracil and accumulated during the G0/G1
cell cycle phase. This cell subtype also exhibited high drug resistance to conventional chemotherapy, which
demonstrates its stem cell-like properties. Limiting dilution and serial transplantation assays revealed that
[31]
the CD71- cell fraction had higher tumorigenicity than the CD71+ cell fraction .

More recently, new tissue stem cell markers have been proposed. Lrig1, which is a marker of proliferative
and quiescent stem cells in the skin and intestine, is a marker of gastric corpus epithelial progenitor cells that
are capable of repopulating the damaged oxyntic mucosa via differentiation into normal gastric lineage cells
in the mouse stomach. Lineage labelling using Lrig1-CreERT2/+; R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+
[32]
(Lrig1/LacZ) mice demonstrated that the Lrig1-YFP-marked cells were gastric progenitor cells . Likewise,
Mist1 is a marker of quiescent stem cells in the gastric corpus isthmus. Mist1-positive stem cells serve as a
cell-of-origin for intestinal-type GCs, and have the combination of Kras and Apc mutations; Mist1-positive
[33]
cells are also the cell-of-origin of diffuse-type GCs when E-cadherin expression is lost . Potential GCSC
markers are summarized in Table 1.

GCSC REGULATION IN THE TUMOR MICROENVIRONMENT
The tumor microenvironment consists of various types of cells including immune cells, endothelial cells, and
fibroblasts, in addition to the extracellular matrix, and has a large impact on tumor progression [34,35] . Cancer
cells remodel their microenvironment through the secretion of growth factors and proteases, while stromal
cells also affect cancer cells through the secretion of soluble factors such as matrix metalloproteinases,
TGF-β1, Wnt ligands, bone morphogenetic proteins, stromal cell-derived factor 1 and exosomes [36-38] . Tissue
stem cells are located beside the surrounding environment termed a “stem cell niche” where they play critical
roles in tissue homeostasis by maintaining their ability to self-renew and differentiate [39,40] .

In the tumor microenvironment, myofibroblasts, which are also known as cancer-associated fibroblasts
(CAFs), share characteristics with smooth muscle cells and fibroblasts. CAFs enhance tumor progression
through the secretion of soluble factors such as growth factors and cytokines in various tumor types [41-43] .