gastric cancer stem cells: a novel therapeutic target

Cancer Letters xxx (2013) xxx–xxx

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Cancer Letters

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Mini-review

Gastric cancer stem cells: A novel therapeutic target

0304-3835/$ - see front matter Published by Elsevier Ireland Ltd.http://dx.doi.org/10.1016/j.canlet.2013.03.035

⇑ Tel.: +1 301 846 7331.E-mail address: [email protected]

Please cite this article in press as: S.R. Singh, Gastric cancer stem cells: A novel therapeutic target, Cancer Lett. (2013), http://dx.doi.org/1j.canlet.2013.03.035

Shree Ram Singh ⇑Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA

a r t i c l e i n f o a b s t r a c t

Article history:Available online xxxx

Keywords:StomachGastric epithelial cellsGastric cancerStem cellsCancer stem cells

Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cellshave been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors knownto promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric can-cer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastrictumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironmentwith normal niche, which play an important role in gastric cancer and tumor growth. This mini-reviewpresents a brief overview of the recent developments in gastric cancer stem cell research. The knowledgegained by studying cancer stem cells in gastric mucosa will support the development of novel therapeuticstrategies for gastric cancer.

Published by Elsevier Ireland Ltd.

1. Introduction

Although the number of cases and the mortality associated withgastric cancer (GC) has recently been declining, it remains thefourth most common cancer and the second leading cause of globalcancer mortality [1]. Every year about one million new patients arediagnosed and 8,00,000 GC-related deaths occur in the world [2].Of all the cases reported, two-thirds occurred in developing coun-tries, with high-risk areas including China, Japan, and Central andSouth America. The American Cancer Society estimates that inthe United States about 21,320 cases of GC will be diagnosed andabout 10,540 people will die from GC in 2012 [3]. The detailedmechanisms that regulate GC are not yet fully understood; how-ever, several factors (environmental and genetic) are reported toplay an important role in promoting GC [4–11]. The environmentalfactors include Helicobacter pylori (H. pylori) infection, foods high insalt, nitrites, smoking, low fiber intake, and a diet low in fruits andvegetables [4,5,7–9,12–17]. In addition to environmental factors,genetic factors such as sex, hereditary diffuse GC (mutation inthe E-cadherin/CDH1 gene), hereditary non-polyposis colorectalcancer (Lynch syndrome), and familial adenomatous polyposis(FAP) also play crucial roles in GC [4,5,7–9,12–17].

Among GC patients, 90% develop adenocarcinoma and only 10%develop lymphoma or a gastrointestinal stromal tumor. Gastricadenocarcinomas include the intestinal (50% differentiated) type,diffuse (33% undifferentiated) type, and mixed (17%) type[9,18,19]. The invasive nature of GC is linked to mutations in sev-eral oncogenes, tumor suppressor genes, changes in several growth

factors and their receptors, epigenetic alterations, altered expres-sion of microRNAs, inflammatory cytokines, and angiogenesis [9–11]. It is estimated that about $1.82 billion each year is spent inthe United States on GC treatment [20]. Regardless of traditionaltreatments such as surgery, radiotherapy, chemotherapy, and tar-geted therapy, the overall five-year survival rate in GC patients isvery low [21].

Recent studies suggest that like other tumors, GC is a heteroge-neous disease [22]. However, the mechanisms that control GCinvasion and metastasis remain to be clarified. It is postulated thattumors develop because of a rare subpopulation of cells (known ascancer stem cells [CSCs]) within a tumor. CSCs have been identifiedin many solid tumors, and they are promising for the developmentof anticancer drugs that can target all CSC subsets within a tumorto prevent recurrence [23]. Because of the failure of traditionaltreatments, CSCs, which already received great attention in thefield of cancer research, are potential novel therapeutic targets inthe treatment of GC. This mini-review presents a brief overviewof the recent developments in gastric stem cell research and therole of CSCs in GC.

2. Gastric epithelial stem cells

2.1. The stomach epithelium

The mammalian gastrointestinal (GI) tract is involved in diges-tion, nutrient absorption, and homeostasis. It also shows the high-est cellular turnover [24,25]. Although human and mousestomachs may be functionally similar, they are different anatomi-cally [25]. Histologically, the human gastric mucosa, which is of

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2 S.R. Singh / Cancer Letters xxx (2013) xxx–xxx

endodermal origin, is divided into three zones: cardiac, fundus/cor-pus, and antral/pyloric [25,26]. Gastric mucosa is also surroundedby subepithelial myofibroblasts (SMFs) [27]. In each gastric zone,the gastric unit is composed of a short pit and a long tubular glandthat subdivides into the isthmus, neck, and base regions [24]. Thecorpus and pyloric zones of the stomach are different in morphol-ogy, cell type, and cellular turnover. The proximal corpus zone con-tains long glands with small pits and several epithelial cell types,such as surface mucous cells (pit), acid-producing parietal cells(oxyntic), mucous neck cells, chief cells (zymogenic), and hor-mone-secreting endocrine cells (gastrin and somatostatin)[25,26,28]. The distal pyloric zone is simple, contains short glandswith a single long pit, and is composed of mucous-producing cells,endocrine cells, and rare parietal cells [25,26,28–30].

2.2. Stem cells in the gastric gland: location, identification, andmarkers

Gastric stem cells (GSCs) play essential roles in the self-renewaland homeostasis of the gastric gland, and they are crucial in epi-thelial repair after injury [24,31,32]. The self-renewal of the humanstomach differs from that of the mouse [25]. In the gastric gland,based on circumstantial morphological and cell kinetic evidence,and in combination with 3H-thymidine-labeling, multipotent stemcells (undifferentiated granular-free progenitors) have been char-acterized at the isthmus region of both the fundic and antral zones[24,25,29,30,33–35]. The multipotent GSCs first differentiated intothree progenitor cells: pre-pit, pre-neck, and pre-parietal cells. Thegranule-free pre-pit cells migrate up towards the lumen to becometerminally differentiated mucous-secreting pit cells. The granule-free pre-neck cells migrate downwards and differentiate intozymogenic/chief cells. In contrast to pit and zymogenic lineages,parietal cells and endocrine cells differentiate within the isthmusfrom pre-parietal cells and migrate up either towards the lumenor down to the gland [24,25,33,34,36–39]. Furthermore, it has beenreported that gastric fundic units are composed of many types ofstem cells [40].

Some of the stem cell markers were detected to label the GSCpopulations [41–45] (Table 1). However, in vivo lineage tracing toidentify such populations was not identified until recently[26,45,46] (Table 1). Qiao et al. [45] found a rare population of qui-escent Villin+ cell resides in the isthmus region of the pyloric zoneof the stomach; however, these cells are not involved in normalgastric gland homeostasis, but are active only in response to dam-age. Recently, Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5), which is considered as a stem cell marker inintestine, colon, and hair follicle and have been reported to expressat the base of the antrum zone of the gastric gland [26]. Further-more, by lineage tracing, Lgr5+ cells have been functionally charac-terized as self-renewing, multipotent stem cells, located at thebase of the glands. They are responsible for the long-term renewalof the gastric epithelium and can also generate self-renewing gas-tric organoids in vitro (Fig. 1) [26,46]. Using lineage tracing withtrefoil factor 2 (TFF2) transgenic lines, Quante et al. [47] demon-strated that TFF2 is restricted to the isthmus region and can pro-duce only mucous neck, parietal, and chief cells. Furthermore,keratin, type I cytoskeletal 19 (Krt19)+ cells have been shownthrough lineage-tracing experiments to label gastric progenitorcells [48]. Mist1, a basic helix-loop-helix transcription factor, is an-other marker identified in the gastric unit, which is expressed inmature chief cells. Lineage-tracing experiments suggest thatMist1+ cells can produce spasmolytic polypeptide-expressingmetaplasia (SPEM) [49,50]. Using Sox2-CreER; ROSA26-lsl-EYFPmice, Arnold et al. [51] performed lineage tracing and found thata small population of Sox2 (sex determining region Y)-box 2)+ cellscan populate the entire glands of both the corpus and pylorus

Please cite this article in press as: S.R. Singh, Gastric cancer stem cells: Aj.canlet.2013.03.035

zones of the stomach, suggesting that Sox2-expressing cells canself-renew and give rise to the mature cell types of the glandularstomach. Recently, it was found that the two zones (fundic and an-tral) of the gastric gland vary because of differences in proliferationand differentiation, as well as in expression profiles [52].

Based on the above experiments, it is clear that gastric mucosaand glands are maintained by bidirectional self-renewal of gastricstem and progenitor cells [25]. Recent studies have suggested thatthe balance between self-renewal and differentiation in gastricmucosa is regulated by several signaling pathways or moleculesuch as wnt, notch, hedgehog, and runt-related transcription factor3 (Runx3) [25,26,28,32,44,46,53–56].

3. Gastric cancer stem cells

3.1. Stem cells and cancer stem cells

Stem cells are functional units of growth that regenerate tissuesand organs and play a role in tissue homeostasis and repair afterdamage or loss [57,58]. Stem cells have the unlimited ability toself-renew and the capacity to differentiate into several specializedcell types. Stem cells reside in a microenvironment called a nichethat protects them from depletion and overproliferation [57,58].Recent studies have shown that tumors contain phenotypicallyand functionally heterogeneous cancer cells. Tumors may originatefrom a small subpopulation of CSCs that are able to maintain long-term tumor growth, tumor recurrence, and apoptosis and chemo-therapy resistance [23,59–62]. CSCs display characteristics thatare similar to normal stem cells, including unlimited self-renewal,proliferation, and multi-lineage differentiation. It is also postulatedthat CSCs occupy the same niche, called the CSC niche, as normalstem cells [63]. The existence of CSCs was first demonstrated byBonnet and Dick [64] from human acute myeloid leukemia (AML)using cell surface markers CD34+/CD38�. Cell surface markers wereused because leukemic stem cells can reproduce the tumor afterserial xenografting into immunodeficient mice. In recent years,accumulating evidence indicates the presence of CSCs in many so-lid tumors, including those in brain cancer [65], breast cancer [66],head and neck cancer [67 and references therein], renal cancer[68], colon cancer [69 and references therein], pancreatic cancer[70], liver cancer [71], melanoma [72], and lung cancer [73].Although many uncertainties have developed in the last few yearsabout the existence of CSCs, recent in vivo evidence suggests thattumors originate from CSCs [74–76].

3.2. Origin, identification, and regulation of gastric cancer stem cells(GCSCs)

3.2.1. Lineage-tracing and expression analysisGastric mucosa is histologically complex and is maintained by

multiple stem cells located in different regions of the fundic andantral zones. It is suggested that GC may originate from normalresident stem cells or bone marrow-derived cells (BMDCs)[26,28,46,77–82]. McDonand et al. [40] provided evidence of intes-tinal metaplasia to dysplasia in human gastric units and found thatintestinal dysplasia is clonal, contains multiple stem cells, andspreads by gland fission. However, the first study to trace the originof GC from stem cells came from the experiments demonstrated byBarker et al. [26]. In this experiment, they tested the tumorigenicpotential of the Lgr5+ pyloric stem cells by injecting a single doseof tamoxifen into Lgr5-EGFP-CreERT2/APCflox/flox mice to activate theLgr5-driven Cre in the pyloric stem cells. Their lineage-tracing re-sults suggest that APC loss in Lgr5+ stem cells efficiently drivesthe rapid appearance of proliferating adenomas in the pylorus zoneof the stomach [26]. Simon et al. [83] further tested the prevalence,

novel therapeutic target, Cancer Lett. (2013), http://dx.doi.org/10.1016/



Table 1Summary of putative gastric stem /progenitor cells and cancer stem cell markers.

Markers Location and function References

Normal stomach Gastric cancer

Villinpromoter

Gland base, antrum of mouse stomach and give rise to all cell types(lineage tracing). Normally quiescent, multiply in response tointerferon gamma

n/t Qiao et al.[45]

Lgr5 Base of pyloric gland, give rise to all cell types (lineage tracing) Luminal surface, tumor centre and invasion front Barker et al.[26]

(Immunostaining, 100 GC patients analyzed) Simon et al.[83]

Mist1 Mature chief cells of corpus gland base in mice and human Give rise to SPEM (lineage tracing using 3 mouse models ofoxyntic atrophy (induced by DMP-777 treatment, L-635treatment, or H felis infection)

Ramsey et al.[50]

Present in the preneoplastic states (normal & gastritis) andlost in neoplasia in human

Nam et al.[49]Lennerz et al.[111]

TFF2 Isthmus region of corpus, gland base (mRNA expression) in mice, giverise to neck, chief and parietal cells only (lineage tracing)

Expressed in SPEM following DMP-777 treatment, due totrans-differentiation of chief cells

Quante et al.[47]

Progressive loss of expression in H pylori-positive gastritis, IMand GC in human and mice

Peterson et al.[112]

DCKL1/DCAMKL1

Isthmus region of corpus (immunostaining) Expression expanded in murine models of acute gastritis,chronic ulcer and in Kras environment

Giannakiset al. [44]Zhang andHuang [97]Kikuchi et al.[98]Okumuraet al. [99]

Musashi-1 Isthmus/neck region of antrum in human stomach(Immunohistochemistry)

Weakly expressed Akasaka et al.[43]

Elevated in gastric lesions and invasive GCs Wang et al.[110]

Sox2 1 and 2 cells above the base of corpus and antrum in mice stomach,give rise to cells in both the corpus and pylorus (lineage tracing)

Expression associated with invasion and lymph nodemetastasis in GC (Immunostaining, 290 GC patients analyzed)

Arnold et al.[51]Matsuokaet al. [100]

Sox9 Weak expression in neck/isthmus of corpus, moderate expression inneck/isthmus of pylorus (immunostaining)

Strong expression observed in GC (46 patients analyzed byimmunostaining)

SashikawaKimura et al.[101]

pSmad2/3L-Thr

Small number of cells in the corpus and antrum, isthmus region(immunostaining)

Significantly increased in the corpus and antrum of mice withHelicobacter-associated gastritis

Fukui et al.[102]

Agr2(anteriorgradient2)

Corpus neck and base of antrum gland (immunostaining) Involve in the development of neoplasia Gupta et al.[103]

Bmi-1 Weak to moderate expression in pits and isthmus of corpus and neckregion of antrum

Strong expression in GC (immunostaining) Reinisch et al.[104]

Oct4 Isthmus region of pit gland, pyloric antrum of human stomach(immunostaining)

Increased expression in GC Al-Marzoqeeet al. [105]

CD44 Strong expression in lower glandular cells of the gastric antrum andrare expression in corpus

Strong expression GC (isolated cells from cancer cell lines andmouse and human gastric samples produce spheroid colonies,and show tumorigenicity)

Takaishi et al.[86]

Wang et al.[110]

CD71-cell n/t Show higher tumorigenicity and multipotency, highlyinvasive and to exist in the invasive fronts of cancer foci

Ohkuma et al.[94]

CD133 Base of gastric glands, antrum Strong expression in GC, expressed on the luminal surfacemembrane of gland-forming cells (patient samples)

Zhao et al.[106]Qiao andGumucio [31]Fukamachiet al. [107]Jiang et al.[92]

Aldh1 Cytoplasm of parietal cells (patient samples-immunostaining) Highly expressed in GC, basal lesion of the metaplastic gland Zhi et al.[149]Wakamatsuet al. [108]

(continued on next page)

S.R. Singh / Cancer Letters xxx (2013) xxx–xxx 3

Please cite this article in press as: S.R. Singh, Gastric cancer stem cells: A novel therapeutic target, Cancer Lett. (2013), http://dx.doi.org/10.1016/j.canlet.2013.03.035



Table 1 (continued)

Markers Location and function References

Normal stomach Gastric cancer

Nishikawaet al. [109]

EpCAM+/CD44+

n/t Isolated cells produce spheroid colonies, and showtumorigenicity

Han et al. [90]

CD44+CD24+ n/t Isolated cells from gastric tissues of patients produce spheroidcolonies, and show tumorigenicity

Zhang et al.[87]

CD44+CD54+ n/t Isolated cells from human gastric tumor tissues andperipheral blood of patients produce spheroid colonies, andshow tumorigenicity

Chen et al.[89]

CD90 n/t Isolated cells from gastric primary tumors produce spheroidcolonies, and show tumorigenicity

Jiang et al.[92]

ABCB1 n/t Highly expressed in poorly differentiated GC Jiang et al.[92]

ABCG2 n/t Highly expressed in poorly differentiated GC Jiang et al.[92]


distribution, and tumor biological significance of Lgr5 cells in thehuman stomach by studying the differential expression of Lgr5 atthe transcriptional and translational levels (Fig. 2A–G). They usedmalignant and non-malignant tissues from different primary tu-mor sites in 127 patients and tested the clinico-pathological signif-icance of Lgr5 expression in 100 patients with GC. Simon et al. [83]found that Lgr5+ cell expression was higher in malignant com-pared to non-malignant tissues. Furthermore, they found the relo-cation of Lgr5+ cells in different stages of GC [83]. They showedthat in non-neoplastic stomach mucosa, Lgr5+ cells were locatedmainly in the mucous neck region; in intestinal metaplasia, thecells were located in the crypt base; and in GC, the cells were lo-cated at the luminal surface, tumor centre, and invasion front(Fig. 2D). Furthermore, Simon et al. found that the tumor centreand invasion front of GC are significantly correlated with local tu-mor growth and nodal spread. Nevertheless, they also found thatpatients with Lgr5+ cells have a shorter median survival rate thanpatients with Lgr5-negative cells GCs. This study suggests that Lgr5could be a general marker of stemness in the GI tract [26,83]. It hasbeen demonstrated that targeted deletion of Klf4 (Kruppel-like fac-tor 4) in Villin + quiescent gastric progenitor cells at the antral mu-cosa induces transformation of the gastric mucosa andtumorigenesis in the antrum in mice [84]. Recently, Quante et al.[85] have shown the presence of Lgr5-labeled cells in the gastriccardia of Lgr5-Cre-ERT mice crossed with Rosa-LacZ reporter miceshortly after tamoxifen induction that within 7 days produceslineage-traced cardia epithelium. Furthermore, when they crossedL2-IL-1b mice with Lgr5-Cre-ERT/Rosa-LacZ mice, they observedlabeled cells in Barrett esophagus (BE) metaplasia within fourmonths of tamoxifen induction, which were treated with bile acidat the ages of 6–8 weeks. The above findings suggest that Lgr5+cells in the cardia possibly function as progenitor cells and serveas the cells of origin for BE and dysplasia. In addition, Quanteet al. also found an accumulation of doublecortin-like kinase 1(Dclk1) + cells near metaplastic mucous-secreting cells in BE tis-sues, since Dclk1 + cells are highly expressed in gastric cardia. Fur-thermore, they also found that Lgr5 and Dclk1 expression wassignificantly elevated in the gastric cardia of BE patients. The aboveexperiments using lineage-tracing and expression analyses suggestthat BE metaplasia in mice and humans may originate from gastriccardia lineage [85].

3.2.2. Cell surface markersThe concept of CSCs may provide a novel approach in GC ther-

apies. Recently, gastric cancer stem cells (GCSCs) have been re-


ported in many GC cell lines as well as in primary tumors usingseveral candidate cell surface markers [22,86–112] (Table 1) anda side population (SP) assay [113–118, but see 119].

3.2.2.1. GC cell lines. Takaishi et al. [86] examined several humanGC cell lines (NCI-N87, AGS, MKN-28, MKN-45, and MKN-74) andfound that CD44 can be used as a potential GCSC marker. They alsofound that a CD44+ cellular fraction isolated from these cell lineshad a sphere-forming capacity, and they found xenograft tumorsin the stomachs of immunodeficient mice [86]. Furthermore, Zhanget al. [87] examined the expression of cell surface markers CD44and CD24 in gastric cell lines and in AGS and GC tissues from fivepatients using fluorescence-activated cell sorting. They identifiedthe tumorigenic properties, the self-renewal, and the differentia-tion between CD44+/CD24+ and CD44�/CD24� cell populationsby in vivo serial transplantation and in vitro culture. They foundthat these cells have the capacity to both self-renew and form tu-mors, which suggests that CD44+/CD24+ can be used as a GCSCmarker. Yang et al. [88] isolated and characterized GCSCs fromGC cell line SGC7901, which has the capacity for in vitro invasionand in vivo metastasis. Furthermore, they found that decreasedexpression of E-cadherin and increased expression of MMP-2 (ma-trix metalloproteinase-2) may be associated with invasion andmetastasis in GCSCs [88]. Recently, aldehyde dehydrogenase 1(ALDH1) was identified as an additional marker for GCSCs by Kat-suno et al. [93] using human GC cell lines. Recently, Liu et al. [95]found that non-adherent spheroid body-forming cells from GC cellline MKN-45, cultured in a stem cell–conditioned medium, con-tained GCSC characteristics of sustained self-renewal, high prolif-eration, resistance to drugs, and high expression of CSC markerssuch as Oct4 (octamer-binding transcription factor 4), Nanog,Sox2, and CD44, compared to parental cells [95].

3.2.2.2. Human GC tissues. Chen et al. [89] isolated CSCs from hu-man GC tissues and the peripheral blood of GC patients usingCD44 and CD54 surface markers. These CD44� and CD54+ cellshave the capacity to generate tumors both in vivo and in vitro.The results from Chen et al. suggest that CD44 and CD54 are poten-tial biomarkers for GCSCs. In another report, using human GC tis-sues, the epithelial cell adhesion molecule (EpCAM) and CD44were identified as putative GCSC markers [90]. Furthermore,CD90 was identified as a potential CSC marker in human gastricprimary tumors [91]. Ohkuma et al. [94] further identified CD71as a potential marker for CSCs in human GC tissues. Recently, alde-hyde dehydrogenase 1 (ALDH1) was identified as an additional




Fig. 1. Adult stem cell-driven epithelial renewal in the pyloric stomach. (A) The location and general architecture of pyloric gastric units, (B) schematic diagram showinggeneration of functional epithelial cells from LGR5+ pyloric stem cells, (C) Cartoon of a self-renewing gastric organoid grown from a single LGR5+ pyloric stem cell. (D) Amodel for LGR5+ stem cell-driven epithelial renewal [Adapted from Barker et al. [46], with permission from Elsevier].


marker for GCSCs by Katsuno et al. [93] using human GC cell lines.Jiang et al. [92] demonstrated the expression of CSC markers ATP-binding cassette sub-family B member 1 (ABCB1), ATP-binding cas-sette sub-family G member 2 (ABCG2), and CD133 in 90 human GCtissue samples and 3 human GC cell lines and concluded that theexpression of these markers varied in GC with various degrees ofdifferentiation; poorly differentiated GC can express a high levelof CSC markers [92].

3.2.3. Side population (SP) assayIn addition to the surface markers named above, studies dem-

onstrated the presence of CSCs in side population (a subset of stemcells) cells isolated from human GC tissues and cell lines. Usingflow cytometry and the DNA-binding dye, Hoechst 33342, Haragu-chi et al. [113] isolated SP cells from many human GC cell lines andfound that the cell lines contained 0.3–2.2% SP cells. Furthermore,Fukuda et al. [114] isolated SP cell populations (ranging from 0.02to 1.93) from human GC cell lines (MKN45, KATOIII, MKN74,MKN28, and MKN1) using flow cytometry. They found that theMKN45 cell line harbored the highest percentage of SP cells be-cause tumorigenesis was shown in vivo. SP cells were isolated byNishii et al. [115] using GC cell lines OCUM-2M, OCUM-2D, andOCUM-2MD3. Nishii et al. found that these SP cells from GC celllines can self-renew and produce non-SP cells and peritonealmetastasis. In addition, they found increased expression of adhe-sion molecules a2, a5, b3-integrins, and b5-integrins, and CD44in SP cells compared to parent cells [115]. Furthermore, Schmucket al. [116] characterized the SP cells from two GC cell lines, AGSand MKN45. They found that SP cells were smaller and expressedCD133 and MSI-1, which produce SP and non-SP cells in recultiva-tion experiments. Their transcriptional analyses showed that SP


cells expressed genes that encoded for stem cell properties suchas FZD7, HEY1, SMO, and ADAM17 [116]. Ehata et al. [117] charac-terized the SP cells within human diffuse-type GC cells isolatedfrom patients and found the amount of SP cells between 1% and4% of the total cells. The SP cells showed greater tumorigenicitythan non-SP cells in vivo. Recently, She et al. [118] analyzed SP cellsand non-SP cells in human GC cell lines KATO III, HS-746T, andAGS. They found that KATO III and HS-746T had high tumorigeniccapacities. KATO III contained 0.57% of SP cells out of the total cellpopulation, and HS-746T contained 1.04% SP cells out of the totalcell population. Only 0.02% SP cells were reported in the AGS cellline. However, She et al. did not find any clear difference betweenSP and non-SP cells when they injected these cells into nude mice[118]. Of note, studies suggest that not all SP cells contain CSCcharacteristics [119]; therefore, the precise identification of CSCsfrom GC cell lines needs to follow the functional assay such assphere formation and xenotransplantation in immunodeficientmice [62,77].

3.2.4. Regulation of GCSCsRecent studies suggest that several signaling pathways includ-

ing hedgehog and wnt/beta-catenin are essential for maintainingGCSCs in human GC [87,120–122]; therefore, understanding theregulation of these pathways represents a justified therapeutic ap-proach to target GCSCs.

3.3. Helicobacter pylori, BMDC, and gastric cancer stem cells (GCSCs)

H. pylori is a spiral-shaped, gram-negative microaerophilic bac-terium that colonizes in the stomachs of almost half of all humans[123]. It is known that H. pylori infection of the stomach results in




Fig. 2. Staining patterns of LGR5 in gastric cancer tissues. (A and E) healthy gastric mucosa, (B and F) intestinal metaplasia, (C and G) gastric adenocarcinoma, with invasionfront (D). (A–D) show representative immunohistochemical staining with an anti-LGR5 antibody on the whole mount sections of intestinal types gastric cancers (GC). (E–G)schematic model of the distributional changes in different stages of gastric tumorigenesis. Arrows mark the LGR5+ cells, astrick (�) marks the luminal site and the black linehighlights the tumor host interface (invasion front). Original magnification 200�. [Adapted from Simon E, [83], with permission from Dr. Christoph Rocken].


stomach inflammation, which leads to step-wise changes such aschronic gastritis, intestinal metaplasia, and ultimately GC [123–125]. H. pylori was isolated by Marshall and Warren in 1984, andit is classified as a class 1 carcinogen [12]. There are four major vir-ulence factors reported from H. pylori: cytotoxin-associated anti-gen A (CagA), cag-pathogenicity island (cagPAI), vacuolatingcytotoxin (VacA), and outer membrane proteins (OMPs). It wasdemonstrated that H. pylori carrying the major protein virulencefactor, CagA, is closely associated with the development of GC[126]. In the last few years, several studies demonstrated the pos-sible interaction between H. pylori, stem cells, and GC[78,82,123,125,127–131]. Recent studies suggest that CSCs existin GC and that these cells possibly originated from resident stemcells, differentiated epithelial cells [26], or stem cells derived fromBMDCs [78]. The existence of CSCs from BMDCs and the interactionbetween these two types of cells were first demonstrated byHoughton et al. [78] using models of Helicobacter-induced cancer.They found that chronic infection of C57BL/6 mice with H. felis re-sults in chronic inflammation and injury in gastric mucosa, whichresults in the loss of resident GSCs and induces BMDC repopulationin the stomach, followed by hyperplasia, metaplasia, dysplasia, andfinally GC [78]. These results from Houghton et al. suggest that Hel-icobacter plays an important role in the progression of GC by mod-ulating stem cells. These results were further confirmed by Varonet al. [82] using a similar mouse model. Furthermore, Giannakis


et al. [128] used a genetically engineered gnotobiotic mouse modelof chronic atrophic gastritis (ChAG) and found that H. pylori couldattach and invade GSCs and that this residency results in GC initi-ation. Ferrand et al. [129] demonstrated that GI epithelial cells in-fected by different strains of H. pylori can influence the migrationof mesenchymal stem cell (MSC) due to the secretion of a combina-tion of cytokines by infected epithelial cells, which are NF-jB (nu-clear factor kappa-light-chain-enhancer of activated B cells)dependent. Recently, Uehara et al. [125] demonstrated the rela-tionship between H. pylori colonization, GC, and DNA damagewithin Lgr5+ epithelial stem cells in the stomachs of patients withGC. They found that Lgr5+ cells expanded in the presence of H. py-lori in the antrum of patients with GC. Furthermore, they foundthat Lgr5+ cells were more susceptible to DNA damage comparedto Lgr5-negative cells, which suggests that H. pylori infection di-rectly affects epithelial stem cells in the stomach, resulting in GC[125]. Similarly, Noto et al. [131] recently found that H. pylori in-duced the expansion of a KLF5+ cell population that was also posi-tive for stem cell marker, Lrig1 (leucine-rich repeat and Ig-likedomain-containing-1). They also found that the degree of KLF5expression increased in parallel with the advancing stages of GCcompared to normal gastric tissue. Recently, Tsugawa et al. [7]used CD44v9-expressing GC cell lines to study the ability of intra-cellular CagA to escape from autophagy, and they found a molecu-lar link between H. pylori–derived CagA and GC stem-like cells. The





studies described above suggest that chronic inflammation be-cause of H. pylori infection plays an important role in transformingresident stem cells into tumor cells.

3.4. GCSC niche and novel therapeutic strategies in GC

Like normal stem cells, CSCs have the capacity for self-renewaland multi-lineage differentiation. Accumulating evidence suggeststhat the behavior of stem cells and CSCs is controlled by a tissue-specific niche microenvironment [23,58,60–63,132–136]. The bal-ance between self-renewal and differentiation of a stem cell isessential for normal tissue homeostasis, which is missing in theCSC niche [137]. There are many components of the niche thathave been suggested to regulate normal stem cell and CSC proper-ties in vivo, and these components are involved in tumor growth,including extracellular matrix, stromal cells, vascular and endothe-lial molecules, secreted modifier proteins, growth factors, bonemarrow-derived myofibroblasts, and hypoxia. In the stomach,GSCs are surrounded by a sheet of subepithelial myofibroblasts(SMFs) that acts as a niche and secretes different types of growthand differentiation factors, including bone morphogenetic proteins(BMPs), transforming growth factor beta 1 (TGF-b1), Wnt ligands,the chemokine stromal-derived factor 1 (SDF), and matrix metallo-proteinases (MMPs) [25,27]. Recently, bone marrow-derived myo-fibroblasts, an important niche component, have been shown to becrucial in GC [80,81,138]. Guo et al. [138] have shown that gastrictumor cells activate stromal fibroblasts (SFs) and become myofi-broblasts, which express vascular endothelial growth factor A(VEGFA) and other angiogenic factors. They suggested that sup-pressing fibroblast activation by inhibiting tumor cell-derived fac-tors would be an effective strategy for the chemoprevention of GC,in combination with the eradication of H. pylori [138]. Shibata et al.[81] showed that overexpression of stromal cell-derived factor-1(SDF-1/CXCL12), a ligand for CXCR4 (C-X-C chemokine receptortype 4), induces GC recruitment of BMDCs and modulation of theprogenitor niche. In addition to myofibroblasts, vascular endothe-lial growth factor (VEGF), TGF-b, vasculogenic mimicry (VM), andhypoxia-inducible factors (HIFs) are critical components of theCSC niche that regulates GC [139–146]. Understanding the originof CSCs and their interaction with niches would be helpful for pre-cisely targeting CSCs.

For many years, conventional anticancer therapies such as che-motherapy, radiation, and immunotherapy have been used, whichcan kill only differentiated tumor cells, resulting in tumor sizereduction; however, the tumors relapse after some time, possiblybecause of the presence of quiescent CSCs, as per the CSC hypoth-esis. In the gastric mucosa, quiescent and active stem cells havebeen reported, which suggests that there is dire need to designdrugs that specifically target CSCs, including stem cell-targetingdrugs, stemness-inhibitor drugs, stemness-promoting drugs, andmicroenvironment-modulating drugs [23,62,74–76,147]. For tar-geting GCSCs, several novel strategies have been suggested, includ-ing a combination of chemotherapy-associated apoptosis, targetedimaging, and tumor stem cell differentiation induction; inducingapoptosis in the tumor; therapies targeting GCSC cell surface mol-ecules; monoclonal antibody development; targeting the GCSCmicroenvironment, inhibition of ABC transporters, telomerasebased therapy and inhibiting GCSC self-renewal pathways[77,81,93,118,122,142,148–160]. Jiang et al. [91] treated gastric tu-mor cells, which express CD90, with trastuzumab (humanizedanti-ERBB2 antibody) and found that trastuzumab can reduce theCD90+ population in tumor size and growth when it is combinedwith traditional chemotherapy. Zhi et al. [149] screened ALDHactivities using several GC cell lines and divided them based onALDH (high) and ALDH (low) GC groups. They found that ALDH(high) cancer cells displayed high CSC properties because they ex-


press higher levels of Sox2, Nanog, and Nestin; they express morefloating spheroid bodies and more colony formation; and they ex-hibit more resistance to traditional chemotherapeutic drugs, 5-Fuand cisplatin (CDDP), compared to those properties found in ALDH(low) cancer cells. In addition, Zhi et al. found that ALDH (high)cancer cells were very sensitive to salinomycin, compared to ALDH(low) cancer cells. This suggests that ALDH could be a potentialmarker of the CSC population in GC and that salinomycin couldbe used as selective therapy for the CSC fraction that is resistantto traditional anticancer drugs, 5-Fu and CDDP [149]. Recently,Akagi [150] examined the roles of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein, in chemotherapy-associated apopto-sis using seven GC cell lines, as well as whether Mcl-1 plays anyrole in apoptosis resistance in CSC-like populations in GC. Akagifound that six out of the seven GC cell lines overexpressed theMcl-1 protein and showed resistance to 5-FU and CDDP. Depletingthe Mcl-1 protein by RNAi results in effectively sensitizing thesecells to anticancer drug-induced mitochondrial cytochrome c re-lease, caspase activation, and apoptosis. Furthermore, Akagi foundthe expression of Mcl-1 mRNA in CD44+ CSC-like cells. ReducedMcl-1 expression enhances apoptosis in CD44+ cells, similar toCD44-negative cells. Akagi’s results suggest that Mcl-1 mediateschemotherapy resistance in CSC-like populations.

Park et al. [154] discussed a near-infrared-sensitive molecularimaging probe based on hydrogel complexes, which can targetGCSC marker, CD44. It has been shown that genetically engineeredstem cells (GESTECs) expressing the cytosine deaminase (CD), asuicide enzyme, and human interferon b (IFN-b) fusion gene hasa synergic antitumor effect on gastric cancer cells [159]. It isknown that MSCs have the capacity to migrate into tumors; there-fore, they can be utilized as potential vehicles cancer therapy. Zhuet al. [160] engineered umblical cord blood mesenchymal stemcells (UCB-MSCs) to deliver a secretable form of LIGHT, a memberof tumor necrosis factor (TNF) superfamily. They found that MSC-LIGHT had a strong suppressive effect on gastric cancer growth,which suggest that this system have the potential to be used asefficient delivery vehicles in the treatment of GCs Zhu et al.[160]. Zhan et al. [157] demonstrated that the expression of orphanreceptor TR3, a regulator of cell proliferation and apoptosis, is ele-vated in gastric tumorsphere cells, which display CSC properties.Loss of TR3 results in reduced stem cell properties in GC cellsand tumorsphere cells, as well as reduced expression of Oct-4and Nanog and the invasion-related gene MMP-9. Zhan et al. iden-tified Nanog as a novel target of TR3. Their data suggest that TR3 isessential for CSC maintenance in human GC cells; therefore, TR3can be used as a new therapeutic target for GC [157]. Althoughthe strategies described above would be helpful in developinganti-CSC drugs to cure GC, not all pathways/markers should be ac-tive in each CSC in tumor tissues. Therefore, early diagnosis anddrugs having multiple targets are crucial to CSCs for treating GCand other types of cancer [60].

4. Conclusions

In summary, accumulative evidence supports the existence ofCSCs that have the capacity to generate tumors, are resistant tochemotherapy, and can produce more differentiated non-tumorigenic cells within gastric tumors. In the last few years, usinglineage tracing and molecular marker labeling, several markersidentified multiple pools of quiescent or active stem cells in gastricunits. Some of these markers are upregulated in GCSCs. In addition,several GCSC populations have been defined, showing that hetero-geneity exists in GC, which suggest that we need to use a combina-tion of biomarkers to target different populations of GCSCs. Studiesalso suggest that CSC behavior is regulated by the niche microen-





vironment. Furthermore, chronic inflammation because of H. pyloriinfection also plays a crucial role in transforming resident stemcells into tumor cells. Dysregulation of several pathways has alsobeen identified in gastric tumor cells. An in-depth understandingof the interaction between GCSCs and their niches, as well as tar-geting stem cell pathways and identifying new candidate therapiesthat target the CSCs, may lead to the development of novel thera-peutic strategies that eradicate GCSC populations, thereby curingGC.

Conflict of interest

The author has no conflicts of interest to disclose.

Acknowledgments

This work was supported by the Intramural Research Programof the National Cancer Institute, National Institutes of Health. Iwould like to thank Dr. Chhavi Chauhan for critical reading andAshley DeVine for editing the manuscript. I apologize to all col-leagues whose relevant contributions were not cited due to spacelimitations.

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gastric cancer stem cells: a novel therapeutic target

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