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CSCs to be widely recognized. CSCs of acute myelogenous leukemia (AML) were first identified by Bonnet
[9]
and Dick in 1997, and they also determined that the CD34+ CD38- fraction of AML tumor cells enhances
tumorigenicity after continuous transplant into immunodeficient mice. CSCs have subsequently been found
in various types of solid tumors [10-12] . Gastric CSCs (GCSCs) have been vigorously investigated in studies
using GC cell lines and primary GC tissues [13-15] .

The current review provides recent evidence for the regulation of GCSCs in the tumor microenvironment
and for GCSC-targeted treatments.

MARKERS OF GCSCS
CD44
CD44 was first identified as a potential GCSC marker in a study using GC cell lines. The CD44-positive
fraction in these GC cell lines showed the ability to form spheroids in vitro and demonstrated tumorigenicity
[16]
in vivo when injected into the stomach wall or when injected subcutaneously into immunodeficient mice .
Furthermore, a combination of the cell surface markers CD44 and CD24 has been examined in GC cell lines
and primary GC tissues from five patients using fluorescence-activated cell sorting. The authors of that study
found that the CD44+/CD24+ fraction demonstrated a higher tumorigenicity compared with the CD44-/
CD24- fraction when injected into immunodeficient mice. Therefore, not only do these cells have the ability
to self-replicate and produce differentiated offspring, the combined expression of CD44+/CD24+ acts as a
[17]
putative GCSC marker . CSCs were isolated from the peripheral blood of GC patients using the cell surface
markers CD44 and CD54, and tumors similar to the original human tumor were generated when the cells
were injected into immunodeficient mice. The same cells differentiated into gastric epithelial cells in vitro
and self-renewed in vivo and in vitro. These results suggest that the combination of CD44+/CD54+ can also
[18]
be used as a potential cell surface marker for GCSCs . Epithelial cell adhesion molecule (EpCAM) and
CD44 have also been identified as CSC markers in various types of tumors. The EpCAM+/CD44+ fraction
from human GC tissues grew into tumors in immunodeficient mice, maintained a differentiated phenotype
and reproduced the morphological and phenotypical heterogeneities of the original gastric tumors. These
[19]
cells acquired greater tolerance to anticancer agents than other subtypes of cells .
Lgr5
Lgr5 has received substantial attention as a new GCSC marker. Initially, Lgr5 was identified in stem cells
within hair follicles, the small intestine, large intestine and stomach [20,21] . Lgr5+ stem cells in the intestinal
crypts are interspersed among terminally differentiated Paneth cells, which act as guardians of the stem cells
[22]
by providing essential niche signals , but the role of Lgr5+ cells in the stomach is not fully understood. In
addition, Notch signaling regulates gastric antral Lgr5 stem cell function. An analysis of gastric organoids
revealed that Notch signaling is intrinsic to the epithelium and that it regulates growth. Furthermore, in one
study, in vivo Notch manipulation affected the efficiency of organoid initiation from glands and single Lgr5-
GFP stem cells, which indicates the regulation of stem cell function by Notch. Moreover, the authors of that
study showed that, compared with control stem cells, stem cells in which Notch signaling was activated
[23]
competed more effectively for niche spots, as they rapidly spread within the stem cell niche . More recently,
Lgr5-positive chief cells were defined as a major cell-of-origin of gastric cancer. That study revealed Lgr5
expression in a subpopulation of chief cells in mouse and human corpus glands. Using a non-variegated
Lgr5-2A-CreERT2 mouse model, the authors demonstrated that the division of these Lgr5-positive cells
depended on the occurrence of Wnt signaling at the time of injury. It has become clear that Lgr5-positive
cells generate all the cells that form the stomach tissue and that they are able to repair wounds within the
stomach. Additionally, it was also found that gastric cancer developed when cancer-associated genes were
activated in Lgr5-positive stem cells. This suggests that tissue stem cells are necessary for the repair and
[24]
regeneration of the injured stomach might change to CSCs . As described above, LGR5 acts as a GCSC
marker of gastric cancer progression.