Gastric stem cells have been recently identified and are not yet fully characterized. Each gastric gland or unit is composed of different specialized cells and a small number of discrete stem cells. These gastric stem cells play key roles. They have self-renewal and multipotent properties and are the origin of specialized gastric epithelial cells. These properties are the basis for the stem cells’ role in tissue homeostasis, tissue repair, and cancer. In tumors, growing evidence indicates that a cell subpopulation with stem cell features, the so-called cancer stem cells (CSCs), represents the “fuel” for the tumor: they are at the origin of tumor initiation, growth, and dissemination, and they also display resistance to conventional chemotherapy treatments. The recent identification of CSCs in gastric carcinoma opens the door to the development of new therapeutic strategies targeting more specifically the CSCs at the origin of the disease, which is the third leading cause of cancer-related deaths worldwide.
- stem cells
- gastric cancer stem cells
- stomach cancer
- Helicobacter pylori
Gastric cancer is the third leading cause of cancer-related deaths and the fifth most frequent cancer worldwide. The cancer in its nonmetastatic form is essentially treated by surgery associated with conventional chemotherapy or by chemotherapy alone when metastatic. Its poor prognosis, with less than 10% survival, is due to frequent relapses in metastatic forms even after multimodal therapy. This relapse is associated with the persistence of a cell subpopulation that has acquired or possesses intrinsic mechanisms to resist chemotherapeutic drugs. Indeed, gastric carcinoma, as other solid tumors, is heterogeneous and, a part of their cell population, the gastric cancer stem cells (GCSCs) are responsible for tumor initiation, progression, recurrence, and metastasis. Herein, we first review the major markers of stem/progenitor cells in the stomach, then we describe the cells at the origin of gastric tumors, and finally, we focus on the characterization of the GCSC subpopulation.
2. Existence of stem cells in the stomach
In the stomach, the gastric epithelium is a physiologically self-renewing tissue with a cycle of 2–7 days. Anatomically, the stomach is divided into three main parts: the cardiac region (in humans) or the forestomach (in mice), the main body (corpus), and the distal part (antrum/pylorus). The mucosa of the stomach is composed of a glandular epithelium with millions of gastric units. Each gland is considered to be monoclonal  and is subdivided into the foveolus, isthmus, neck, and bottom regions (Figure 1). In the gastric corpus, the glands are long and, from the bottom to the top of the gland, contain zymogenic/chief cells implicated in digestion, parietal cells that are essential for acid production, enterochromaffin-like cells that control acid production, mucous neck cells, and superficial pit cells. In the antrum, the glands are shorter and are composed mainly of mucus-producing cells and enteroendocrine hormone-secreting cells that regulate acid and digestive enzyme production in the corpus. In both regions, some discrete gastric stem cells exist and are instrumental in stomach epithelium renewal under pathophysiological conditions.
In adult organs, tissue stem cells are characterized by self-renewal and asymmetrical division properties, giving rise after mitosis to another stem cell and to a progenitor cell that will undergo expansion and then differentiation into mature cells. These stem cells reside in a physiologically limited and specialized microenvironment, called the niche, which is comprised of cells and extracellular matrices forming the surrounding stroma (including mesenchymal cells, vessels, nerves) and which plays a key role in the maintenance of the stem cell number and functions and in preventing tumorigenesis. The localization of the niche of stem/progenitor cells varies according to the part of the stomach considered: in the corpus, they are located in the isthmus just below the glandular narrowing, and in the antropyloric region, there are located at the bottom of the glands. Moreover, as is the case in other organs , the coexistence of two stem cell populations has been described in the stomach: (1) a population of dividing gastric stem cells recruited under “homeostatic conditions”, expressing CD44 or Lgr5 markers and (2) a rare population of quiescent cells recruited mainly upon tissue damage, expressing Villin, Troy, and Mist1 markers (Figure 1).
2.1. Discovery of gastric stem cells and their markers
Using radiolabeling experiments and analyses of the cells by electron microscopy, Leblond et al. first identified a group of small undifferentiated and granule-free cells with the highest labeling index as the putative stem/progenitor cells. These cells are localized in the isthmus region from where they migrate toward both the pit and the bottom [3, 4]. However, the first evidence of the existence of multipotent stem cells in adult mouse gastric glands was found later using chemical mutagenesis of single cells and long-term gastric epithelial cell analyses where many clones spanned entire glands containing all specialized gastric cell lineages . The use of inducible Cre recombinase activity to indelibly label putative stem/progenitor cells and their progeny in the stomach has been widely practiced and is considered as the gold standard method for lineage tracing studies. The first marker of gastric stem/progenitor cells revealed by lineage tracing in the gastric mucosa was
Leucine-rich G protein-coupled receptor 5 (
These two markers identified stem cells in the gastric antrum/pyloric region, where most of distal gastric carcinoma arises in humans. In the corpus, some studies suggested that
In addition, the Runx1 enhancer element,
Additional markers have been proposed for gastric stem cells (e.g., DCKL1/DCAMKL1, CD133/PROM1, and CD44), but the multipotency of these cells has not yet been analyzed by lineage tracing [15, 16]. Khurana et al. found that
2.2. Factors sustaining gastric stem cell self-renewal and multipotency
Until very recently, suitable models to study gastric stem cells in vitro were lacking. Cell lines from cell banks are all derived from carcinomas, and primary culture of gastric epithelial cells from biopsies is not successful under conventional adherent culture conditions. Culture of antrum and fundus cells has been rendered possible very recently by the development of mouse and human protocols allowing the development of organoids, named gastroids, under three-dimensional culture conditions, in media containing epithelial growth factor (EGF) and Noggin, with either Wnt3A and R-spondin, a molecule binding Lgr4/5 and potentiating Wnt/β-catenin activity , or supplemented with the Notch ligand Jagged-1 [7, 13]. In vitro studies of organoid formation by gastric stem cells or gastric glands have allowed insight in the necessary growth factors and signaling molecules of the niche implicated in stem cell properties and gland formation and can offer new therapeutic applications in patient that suffer malignant diseases, for example, for ulcer treatment. Engevik et al. have shown that gastric stem cells/organoid isolated from young mice can be transplanted into sites of acetic acid-induced ulcer within the stomachs of older mice and that this results in accelerated repair injury .
Wnt5a, a noncanonical Wnt ligand, is highly expressed by Cxcr4+ cells in the isthmus part of the corpus. Histological analyses show that Wnt5A is secreted by Cxcr4+ resident hematopoietic cells recruited to the isthmus and stimulated by Cxcl12 endothelial cell production. The efficiency of organoid formation is enhanced by Wnt5a or coculture with Cxcr4+ intraepithelial gastric innate lymphoid cells , suggesting that cells in the niche regulate stem/progenitor proliferation.
The enteric nervous system also has the ability to regulate gastric homeostasis via direct innervation of the glands. In three independent mouse models of gastric cancer, Zhao et al. elegantly demonstrated that surgical or pharmacological denervation suppresses gastric tumorigenesis, even if performed at an early preneoplastic step . Further analyses revealed that cholinergic nerves surround the base of glands and modulate epithelial stem cells through activation of the Wnt signaling pathway via the muscarinic acetylcholine receptor 3 (M3R) expressed by Lgr5+ cells. In stomach organoid models, coculture with neurons or treatment with pilocarpine, a cholinomimetic drug, increased organoid formation and the expression of
The Notch signaling pathway is also inhibited in vagotomized mice . The Notch inhibitor dibenzazepine (DBZ) reduced the proliferation in the isthmus region, decreased the Mist1-lineage tracing, and blocked the growth of corpus organoids in vitro, suggesting that Notch activity is important for corpus gastric stem cell maintenance and activity .
3. Is gastric cancer a stem cell disease?
Gastric carcinoma is a multifactorial disease, involving a chronic
More than 93% of distal gastric carcinoma cases are associated with a chronic
3.1. Tumors can originate from epithelial stem cell transformation
Interestingly, the parietal cell atrophy induced after
KRAS is one of the most commonly mutated oncogenes in gastric cancer. The
E-cadherin expression is lost in most diffuse-type gastric carcinomas, but E-cadherin loss alone is not sufficient to initiate diffuse-type gastric cancer in mice . Loss of the tight junction protein IQGAP1 is also insufficient to induce diffuse-type gastric carcinoma in transgenic mice after challenge with
3.2. Tumors originating from bone marrow-derived cells
Some data have shown that bone marrow-derived cells (BMDCs) can migrate to peripheral tissues in case of injury or inflammation where they are engrafted and participate in tissue repair, giving rise to all cell lineages. Houghton et al. showed that BMDCs are recruited into the gastric mucosa of C57BL/6 mice chronically infected by
Unfortunately, in those models, full proof of the concept that gastric stem cells or other populations of differentiated cells or BMDCs are the cells of origin of cancer has not been found, because the tumorigenic effect mediated, for instance, by
3.3. Tumor originates from dedifferentiation of epithelial cells
In an inflammatory setting, differentiated cells can reacquire the ability to divide and to give rise to all cell lineages. In vitro,
4. Properties of gastric cancer stem cells
Tumor cells are heterogeneous in terms of mutations carried, susceptibility to drugs, markers expressed or morphology, and not all are tumorigenic. This genetic heterogeneity would come not only from intrinsic factors such as genetic mutations acquired progressively and amplified within new clones but also from extrinsic factors related to the variation of the tumor microenvironment [54, 55]. To explain these observations, two concepts have been proposed: the cancer stem cell (CSC) theory, also named the hierarchical model, and the stochastic model. In the stochastic model, all cancer cells have similar tumorigenic properties, with cancer arising after a series of genetic and epigenetic events leading to successive waves of clonal selections depending on the proliferative and survival benefits acquired. In the hierarchical model, there is a cellular hierarchy between cancer cells inside the tumor, with CSCs being at the origin of the more or less differentiated cells, not all proliferative and tumorigenic, composing the tumor mass. CSCs represent a small percentage of tumor cells and possess particular properties compared to non-CSCs (Figure 3): (1) the first and most important is their capacity to self-renew and divide asymmetrically and to generate a new CSC and a non-CSC progenitor cell, a property that maintains a constant CSC pool; (2) CSCs are able to initiate tumor growth when injected in low cell numbers in immunocompromised mice; (3) CSCs display differentiation properties giving rise to the more or less differentiated cells composing the tumor mass, reconstructing the tumor heterogeneity observed within the primary tumor; (4) CSCs have increased resistance to current chemo- and radiotherapies; and (5) CSCs express specific markers . This hierarchical model is not exclusive but is now the most accepted model with the recent identification of CSCs in most cancers since their first discovery in acute myeloid leukemia in 1995, then in solid tumors in 2003, and more recently in gastric carcinoma. However, we must keep in mind that this hierarchical model is also subjected to clonal evolution even if it has not been clearly demonstrated for gastric carcinoma .
4.1. Functional characterization of gastric cancer stem cells
By taking advantage of the capacity of stem cells to self-renew, differentiate, and initiate tumors, functional assays have been developed to evaluate the amount of GCSCs or to isolate them from a global population of tumor cells. In vitro, under conditions in which cells are seeded at low-density in low-adherent plates, without serum and in the presence of some growth factors such as EGF, bFGF, and insulin, only GCSCs can survive, self-renew, and form tumorspheres [36, 50, 51, 57]. Long self-renewal ability is evaluated after tumorsphere dissociation into single cells and several passages; indeed only GCSCs can generate tumorspheres after several passages [51, 58]. In vivo, frequency of GCSCs in a given population is determined after subcutaneous xenograft in immunocompromised mice using different cell doses and an analysis of their ability to initiate a new heterogenous tumor after several weeks. Immunocompromised mouse phenotypes, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) and NOD/SCID/IL2Rg− (NSG), can influence the CSC frequency as reported in the case of melanoma by Morrison’s group . In both methods, cells were seeded for an extreme limiting dilution assay, and a mathematical method was applied to calculate the CSC frequency in a given cell population [51, 60].
4.2. Phenotypic characterization of gastric cancer stem cells
Several phenotypic characteristics have been proposed to isolate GCSCs using fluorescence-activated cell sorting (FACS), including (1) the expression of cell membrane markers (or combinations of markers), and among them CD44; (2) the exclusion of Hoechst 33342 dye by the “side population” of cells (SP cells); and (3) the enzymatic activity of aldehyde dehydrogenases (ALDH).
Takaishi et al. were the first to propose CD44 as a marker of GCSCs in a study performed on several gastric cancer cell lines . Their CD44+ cells were able to form tumorspheres and initiate tumors after subcutaneous and orthotopic engraftment in mice, and they were resistant to anticancer drugs, whereas CD44− sorted cells were not. Moreover, it seems that CD44 is not only a GCSC marker, but it also plays an oncogenic role, assessed by a decrease in tumor growth using siRNA targeting CD44. More recently, further relevant results from patient-derived xenograft models (PDXs) of gastric carcinoma have confirmed that CD44 is also a marker of GCSCs in primary gastric carcinoma. The FACS-sorted CD44+ cells, but not their CD44− counterpart, displayed CSC properties such as growing as tumorspheres in vitro and lead to tumor formation in vivo that reconstitute the heterogeneity of the primary tumor of the patients and are more chemoresistant [51, 71, 72]. ESA, CD24, CD133, and CD166 are also expressed by CD44+ cells, but they do not allow a better enrichment of GCSCs in combination with CD44 compared to CD44 alone [51, 73]. Although CD44 marks GCSCs, not all CD44+ cells are tumorigenic . CD44v8-10, also named CD44E, has been identified as the predominant CD44 variant expressed in gastric cancer cells, and its expression is low in normal tissues . It plays a functional role in tumor initiation, most likely by increasing CSC resilience to adverse conditions such as hypoxia or oxidative stress. Indeed, there is evidence that CD44v8-10 stabilizes the cystine-glutamate transporter subunit xCT and promotes the synthesis of glutathione, thereby protecting cancer cells from reactive oxygen species . Depletion of the expression of CD44 leads to a decrease in the tumorigenicity of cancer cell lines , and Yoon et al. demonstrated implication of the Hedgehog signaling in the maintenance, chemoresistance, and migration capacity of the GCSC CD44+ cells .
4.3. Missing data: implication of gastric cancer stem cells in metastasis?
Another important property of CSCs is their ability to initiate metastasis. Metastasis is a rare event  requiring the acquisition of invasive properties through epithelial-mesenchymal transition (1) to escape from the niche of the primary tumor in order to disseminate to distant organs after extravasation as circulating tumor cells (CTCs) and (2) to initiate secondary tumors . We reported that the CD44+ cells with CSC-like properties induced by
Since 2007, researchers have increased efforts to identify real gastric stem cells, the cell population capable of replenishing an entire gastric gland containing of all cell lineages. Many of the markers involved have been reviewed here, and their stemness properties have been clearly demonstrated in mouse models. It will be of interest to understand why there are different localizations of stem cells, one in the isthmus and one at the bottom of the gland. These two stem/progenitor cell niches could play different roles, one being more proliferative than the other one which seems to behave like a reservoir, but they could also play distinct roles in response to different stimuli and damage to the gastric mucosa.
Regarding to the gastric tumor, an in-depth analysis of putative CSC markers identified CD44 as well as ALDH activity as the “gold” gastric CSC markers in cancer cell lines and in PDX models . Determination of the signaling pathways controlling their properties is now instrumental to find new targeted therapies for gastric cancer, for which there is a crucial unmet need to find new efficient therapy. In this aim, we have shown by different strategies that the targeting of gastric CSCs expressing CD44 by blocking specific microRNAs or by inducing their differentiation by all-trans retinoic acid allows inhibition of tumor growth in vivo [58, 83].
Nevertheless, the characterization of gastric CSCs was limited in some publications by the cellular model used. To date, the best models to study the efficiency of new therapeutic strategies on primary gastric CSCs remain PDX models, with the restriction that almost all of those described are subcutaneous engraftments which never give rise to metastasis. Moreover, mouse models of gastric carcinogenesis induced by
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