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Abstract

Gastric cancer is a leading cause of cancer-related mortality worldwide. Cancer stem cells are the source of tumor recurrence and metastasis. Self-renewal is a marker of cancer stem cells and also the basis of long-lasting survival and tumor progression. Although the mechanism of gastric cancer stem cell self-renewal is not clear, there are several signaling pathways and environmental factors known to be involved. This mini review describes recent developments in the self-renewal signaling pathway of gastric cancer stem cell research. Advancements made in this field of research will likely support the development of novel therapeutic strategies for gastric cancer.

Keywords

Gastric cancer cancer stem cells self-renewal signaling pathways

Introduction

Gastric cancer is a common malignancy as it is regarded as the second leading cause of cancer-related death worldwide.¹ Although progress has been made with respect to the diagnosis and treatment of gastric cancer, major questions remain unanswered. The literature suggests the presence of gastric cancer stem cells (GCSCs) or tumor-initiating stem-like cells. GCSCs are a small population of cells present in the tumor that are capable of self-renewal and generation of differentiated progeny. The presence of GCSCs in a tumor is associated with treatment failure, as these cells are believed to be the source of cancer survival, recurrence, metastasis, and drug resistance. Therefore, increasing attention has been given to GCSC research to increase therapeutic efficacy. Cancer stem cells (CSCs) are characterized by their ability to self-renew. Targeting the self-renewal of GCSC may be a novel therapeutic strategy in gastric cancer. However, the molecular mechanisms underlying the self-renewal of GCSCs are poorly characterized. This review presents a brief overview of the signaling pathways essential to GCSC self-renewal.

GCSCs

Identification of GCSCs

After the demonstration of CSCs in leukemia by John Dick’s group, CSCs were successfully isolated from numerous solid cancers.^2,3 Presently, the literature strongly supports the presence of CSCs, or tumor-initiating stem-like cells, and defines CSCs as a small population in tumor that are capable of self-renewal and generation of differentiated progeny.⁴ In 2009, Takaishi et al. identified gastric cancer–initiating cells from a panel of human gastric cancer cell lines using the cell surface marker CD44. CD44(+) cells from MKN-45, MKN-74, and NCI-N87 showed spheroid colony formation in serum-free media in vitro. It also had the tumorigenic ability when injected into stomach and skin of severe combined immunodeficient (SCID) mice in vivo. The CD44(+) gastric cancer cells not only maintained self-renewal but also gave rise to CD44(−) cells, illustrating the ability to give rise to differentiated progeny. CD44 knockdown by short hairpin RNA resulted in significantly reduced spheroid colony formation and smaller tumor production in SCID mice. In addition, the CD44(−) populations had significantly reduced tumorigenic ability in vitro and in vivo. These results support the existence of GCSCs.⁵

Notably, emerging evidence suggests that non-CSCs can be induced into a transient and drug-tolerant CSC-like state by chemotherapy, tumor progression, hypoxia, epithelial-to-mesenchymal transition (EMT), inflammation, microenvironment changes, and experimental manipulation.^6,7 Moreover, the acquisition of genetic and epigenetic alterations in GCSC can contribute to the generation of intra-tumoral heterogeneity.

Origin of GCSCs

Two hypotheses exist about the origin of GCSCs. The first is that GCSCs are derived from gastric stem cells (GSCs). GSCs have been identified in the epithelium of the corpus and antrum of the stomach.⁸ Lineage tracing experiments demonstrated that stem cell in the isthmus and antrum continuously gave rise to mature cell to maintain the gastric unit.⁹ GSCs seem to reside at the gland bottom and push their differentiating progeny up toward the gland.¹⁰ Gastric cancer development will ensue following mutation of GSCs. Subsequently, a chain of transformations will result from normal gastric mucosa to atrophic gastritis, intestinal metaplasia, atypical hyperplasia, and finally to gastric cancer. Alternatively, the second major hypothesis proposes that GCSCs are derived from bone marrow–derived mesenchymal stem cells (BM-MSCs).¹¹ In mice infected by Helicobacter pylori, a model of inflammatory stimulation, BM-MSCs with Y-chromosome positive migrate to the gastric epithelium and differentiate into cancerous cells.¹²

GCSC markers

GCSCs can be isolated and identified using a number of methods, including sphere forming assay, Hoechst dye exclusion assay, fluorescence-activated cell sorting (FACS), magnetic cell sorting (MACS), and transplantation assays.¹³ MACS and FACS are widely used to isolate cells based on biomarkers. A large number of surface markers in GCSCs have been identified and confirmed. The main markers used for isolation and identification of GCSCs include Villin, Lgr5, Tff2, Mist1/Bhlhal5, Dclk1, Prom1/CD133, CD44, CD90, and ALDH1. The GCSC markers reported to date are summarized in Table 1. Importantly, a consensus has not been reached that it is recommended to use two or more markers to separate and identify GCSC. Moreover, at different stages of differentiation, it is possible that cell surface molecules on GCSC may also differ.

Table 1.

Biomarker of gastric cancer stem cell.

Cell surface marker	Tumor location	Reference
Villin	Antrum	Park et al.¹⁴
Lgr5	Gastric antrum gastro-esophageal junction	Li et al.¹⁵
Mist1/Bhlhal5	Gastric corpus isthmus	Hayakawa et al.¹⁶
Dclk1	Fundic glands, antrum	Choi et al.¹⁷
Prom1/CD133	The entire base of antral glands	Qiao and Gumucio¹⁸
CD44+	Widely expressed	Zhang et al.¹⁹
CD90+	(Identify in cell line)	Jiang et al.²⁰
ALDH1+	(Identify in cell line)	Nguyen et al.²¹

Self-renewal signaling pathways utilized by GCSCs

In normal stem cells, self-renewal pathways are strictly regulated. In contrast, self-renewal pathways in CSCs are significantly dysregulated. In bulk tumors, only the CSC population can self-renew, meaning that CSC can produce additional CSC as well as clonal daughter cells through asymmetric and symmetric cell division. The self-renewal of CSC guarantees their long-term survival. During progression, cancer cells may accumulate additional mutations through the self-renewal process. The ability of self-renewal in CSC is not fixed, where in some conditions, it can actually be enhanced, weakened, acquired, or even lost. Notably, several factors and key signaling pathways have been implicated in the regulation of GCSC self-renewal.

Wnt signaling

Wnt signaling plays an important role in cell proliferation, survival, self-renewal, and differentiation in normal adult stem cells. It also appears to be involved in the regulation of GCSC as well, and aberrant regulation of this pathways leads to neoplastic proliferation and tumor formation. When Wnt signaling was overexpressed in gastric epithelial cells, gastric epithelial cell dedifferentiation, fundic gland polyp (FGP) formation and adenomatous change were observed.²² Sarkar et al.²³ identify Sox2 is dispensable for GSC and epithelial self-renewal but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes. Sox2 suppresses Wnt/β-catenin signaling. Sox2 loss enhances gastric tumorigenesis. Yong et al. found that H. pylori–infected gastric cancer cells induced CSC-like properties, including an increased capacity for self-renewal. Further studies revealed that H. pylori activated Wnt/β-catenin signaling pathway. They further demonstrated that this activation was responsible for H. pylori–induced CSC-like properties.²⁴ Song et al.²⁵ also affirmed Wnt/β-catenin pathway involved in H. pylori–induced GCSC generation. In GCSCs, Wnt/β-catenin axis has been reported to play a vital role in the self-renewal. Cai et al. provided the first evidence that the Wnt/β-catenin pathway is essential for the self-renewal of CSCs in human gastric cancer. Blockage of the pathway, DKK-1, caused a significant reduction in the self-renewal capacity of MKN-45 tumor sphere cells (SCs), and activation of the pathway by lithium chloride improved the CSC self-renewal.²⁶ Mao et al. reported that salinomycin, an antitumor agent, significantly reduced tumor volume of Wnt1-overexpressing AGS cells in vivo. In this context, suppression of Wnt1 and β-catenin expression resulted in inhibition of the proliferation of the CD44+Oct4+ CSC subpopulation.²⁷ Wu et al.²⁸ found that miR-19b, miR-20a, and miR-92a could sustain the self-renewal function of GCSCs, and miR-17-92 has been shown to target the E2F1 and HIPK1 proteins which suppressed Wnt/β-catenin signaling. Bie et al.²⁹ indicate that the interleukin (IL)-17B/IL-17RB signal can promote the growth and migration of tumor cells and upregulate cell stemness through activating the AKT/β-catenin pathway in gastric cancer. Finally, evodiamine (Evo), a derivative of the traditional herbal medicine Evodia rutaecarpa, inhibited the Wnt/β-catenin signaling pathway, resulting in reduced proliferation and stem-like properties of GCSCs.³⁰ In addition, anti-cancer drug 3,3′-diindolylmethane activated Wnt4 signaling, enhancing gastric cancer cell stemness and tumorigenesis.³¹

Sonic hedgehog signaling pathway

Many studies have suggested that hedgehog signaling induces the differentiation of GSCs in the adult stomach.^32,33 The aberrant activation of this pathway may contribute to tumorigenesis in human gastric cancers, as recent reports have suggested that the Sonic hedgehog (SHH) signaling pathway plays a crucial role in self-renewal.^34,35 Furthermore, Donnelly et al.³⁶ found SHH, secreted from BM-MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation. Song et al. investigated the possibility that abnormal activation of the SHH pathway helped maintain the characteristics of gastric CSCs. Their analysis revealed that SHH pathway blockade by cyclopamine or 5E1 significant reduced the self-renewal capacity of HGC-27 tumor spheres compared to adherent cells controls.³⁷ Importantly, additional findings confirmed that the SHH-Gli signaling pathway is involved in the drug resistance conferred by GCSC.^38,39 In addition, in lung squamous cell carcinoma, glioma, colon cancer, and SHH signaling can maintain the self-renewal of CSCs through regulating the expression of Oct4, Sox2, and Bmi1.^40–42

Transforming growth factor-β/Smad signaling pathway

The transforming growth factor-β (TGF-β) signaling pathway has an important role in the regulation of embryonic stem cell (ESC) activity and organ formation. Smad proteins are the downstream signaling transducers of the TGF-β signaling pathway. In vertebrates, at least nine Smad proteins have been identified to date, namely, Smad 1–9, and each has a different function. Choi et al.⁴³ found H. pylori infection may trigger the TGF-β1-induced EMT in gastric mucosa and the emergence of GCSCs. Donnelly et al.⁴⁴ revealed that BM-MSCs promote GCSCs through TGF-β signaling in response to gastritis. Yu et al. found that increased expression of the miR-106b family, comprising miR-106b, miR-93, and miR-25, regulated cancer stemness through the TGF-β/Smad signaling pathway in CD44(+) GCSC. In a microRNA (miRNA) microarray analysis, expression of the miR-106b family was significantly upregulated in CD44(+) cells. The miR-106b family targeting Smad7, which inhibits TGF-β/Smad signaling, was downregulated in CD44(+) cells. Furthermore, expression of key TGF-β/Smad signaling molecules were shown to be activated in CD44(+) cells, in accordance with the action of the miR-106b family. Inhibition of miR-106b suppressed the TGF-β/Smad signaling pathway and decreased both self-renewal capacity and cell invasiveness.⁴⁵ Fujita et al.⁴⁶ demonstrated that treatment with TGF-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation, or asymmetric cell division of the CXCR4-positive gastric CSCs, even in a dormant state.

Hippo-YAP signaling pathway

The Salvador-Warts-Hippo pathway controls cell fate and tissue growth. The main function of the Hippo pathway is to prevent YAP and TAZ translocation to the nucleus where they induce the transcription of genes involved in cell proliferation, survival, and stem cell maintenance. The Hippo pathway plays an important role in tumor suppression, and, consequently, its deregulation is a key feature in many cancers.⁴⁷ The Hippo pathway regulates tumorigenesis by inhibiting cell proliferation, promoting apoptosis, and regulating stem and progenitor cell expansion.⁴⁸ The activity of YAP/TAZ is required to sustain self-renewal and the tumor-initiating capacity of CSC. Findings from Fujimoto et al.⁴⁹ suggest that the activation of protease-activated receptor 1 (PAR1) contributes to multi-drug resistance and tumorigenesis through interaction with the Hippo-YAP pathway to confer self-renewal in GCSC. However, the precise mechanism whereby the Hippo pathway helps maintain GCSC has not been well understood or described and therefore warrants further investigation. Notably, YAP/TAZ activation can sustain self-renewal and tumor-initiation capacity of human breast cancer.⁵⁰

Nuclear factor kappa B signaling pathway

Nuclear factor kappa B (NF-κB) is a family of transcription factors (TFs). As an early TF, activation of NF-κB does not require the synthesis of new proteins and can therefore respond readily to harmful stressors. When the IκB kinase (IKK) receptor is activated, the phosphorylation inhibitor protein causes liberation of NF-κB, which enters into the nucleus and modulates gene transcription. Aberrant expression of NF-κB has been linked to cancer development and progression. Zhu et al.’s⁵¹ findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GCSC phenotype and function depending on NF-κB p65 activation. Moreover, NF-κB has been shown to play a role in the self-renewal of GCSCs. Han et al.⁵² found that cancer-associated fibroblasts (CAFs) increased the self-renewal capacity of GCSCs by secreting NRG1, which activated NF-κB signaling to regulate GCSC self-renewal. Echizen et al.⁵³ reported that H. pylori infection stimulates innate immune responses through Toll-like receptors (TLRs), inducing cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway, an important pathway in the maintenance of stemness in GCSC, through NF-κB activation. These findings are supported by multiple reports demonstrating that aberrant activation of NF-κ B signaling can promote self-renewal in breast, prostate, and glioma CSCs.⁵⁴

Notch signaling pathway

Notch signaling regulates differentiation status in the intestinal epithelium stem cells.⁵⁵ However, abnormal activation of Notch signaling is implicated in the self-renewal of various CSCs.⁵⁶ Although there is no direct evidence supporting the roles of Notch signaling in GCSCs, abnormal activation of Notch signaling was observed in gastric cancer.⁵⁷ Chronic Notch activation induced undifferentiated, hyper-proliferative polyps, suggesting that aberrant activation of Notch in GSCs may contribute to gastric tumorigenesis.⁵⁸ About 75% of primary gastric cancers express the Notch ligand Jag1. Activation of the Notch1 signaling pathway is associated with gastric cancer progression through COX-2.⁵⁹ Another study show that AT-I attenuated GCSC traits partly through inactivation of Notch1, leading to reduced expression of its downstream targets Hes1, Hey1, and CD44 in vitro.⁶⁰ Zhu et al. find that NOTCH2 is activated in liver CSCs. C8orf4, located within the cytoplasm of hepatocellular carcinoma (HCC) tumor cells, associates with the intracellular domain of NOTCH2, which impedes the nuclear translocation of N2ICD. C8orf4 deletion causes nuclear translocation of N2ICD, triggering NOTCH2 signaling and sustained stemness of liver CSCs.⁶¹

TFs

The gene regulatory circuitry through which pluripotent ESCs choose between self-renewal and differentiation appears complex. Interestingly, Dunn et al. proposed that propagation of ESC identity is not determined by a vast interactome, but rather is explained by a relatively simple process of molecular computation. The simplest version or minimal set comprises only 16 interactions, including 12 TFs and three inputs, and satisfies all prior specifications for self-renewal.⁶² In ESC, KDM5B, a histone H3 trimethyl lysine 4 (H3K4me3) demethylase, is a downstream Nanog target and critical for ESC self-renewal.⁶³ Notably, Stem cell–specific TFs, like Sox2, Oct4, Klf4, and Nanog, are frequently encountered in human cancers and their transcriptional networks are necessary for the development and maintenance of cancer stem-like cells.^64,65 Tian et al. isolated GCSCs from human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, HGC-27, and MKN-28 using side population (SP) sorting method and subsequently cultured the SC for characterization. The small interfering RNA (siRNA)-mediated downregulation of Sox2 noticeably reduced spheroid colony formation in vitro and suppressed tumorigenicity in vivo. The results suggest that Sox2 plays a pivotal role in sustaining stem cell properties in GCSC.⁶⁶

Microenvironment

Current evidence suggests that the characteristics of CSCs, including self-renewal, are controlled by the surrounding microenvironment, referred to as the “cancer stem cell niche.” CSCs in the stomach are surrounded by diverse cell lineages, including endothelial cells, hematopoietic cells, and BM-derived myofibroblasts, as well asvasculature, and extracellular matrix (ECM).⁶⁷ Cells in the niche secrete different types of growth and differentiation factors, leading to the unbalance between GCSC self-renewal and differentiation.^68–70 Liu et al.⁷¹ found simulating the microenvironment of gastric cancer can promote the malignant transformation of BM-MSCs. Hayakawa et al. found Mist1(+) stem cells serve as a cell-of-origin for diffuse-type gastric cancer. Inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs) is also involved in diffuse-type gastric cancer development.¹⁶ Hypoxia is known to play pivotal roles in the maintenance of self-renewal and the undifferentiated state of CSCs in various solid tumors. Guo et al.⁷² demonstrated that hypoxic microenvironments induce EMT and increase stem-like properties of gastric cancer cells. Miao et al. also found peritoneal milky spots (PMSs) served as a hypoxic niche and favored gastric cancer stem/progenitor cells (GCSPCs) peritoneal dissemination through hypoxia-inducible factor 1α (HIF-1α). Furthermore, the GCSPC population expanded in primary gastric cancer cells under hypoxic condition in vitro, and hypoxic GCSPCs showed enhanced self-renewal ability, but reduced differentiation capacity, mediated by HIF-1α.⁷³

CAFs have recently been implicated in stemness of gastric cancer cells. Hasegawa et al. found CAFs could regulate the stemness of CSCs in scirrhous gastric cancer. CAF significantly increased the percentages of the SP fraction of scirrhous gastric cancer cell lines, OCUM-12 and OCUM-2MD3. CAF significantly increased the number of spheroid colonies and the expression level of CSC markers of OCUM-12/SP and OCUM-2MD3/SP cells. These stimulating activities by CAF were significantly decreased by TGF-β inhibitors. These findings suggested that CAFs might regulate the stemness of CSCs in scirrhous gastric cancer by TGF-β signaling.⁷⁴ Besides, CAF stimulates EMT and cancer stemness in prostate cancer. Activated fibroblasts through secretion of metalloproteinases elicit a clear EMT in prostate cancer cells, as well as enhancement of tumor growth and development of spontaneous metastases. CAF-induced EMT leads prostate cancer cells to enhance expression of stem cell markers, as well as the ability to form prostaspheres and to self-renew. Hence, the paracrine interplay between CAFs and cancer cells leads to an EMT-driven gain of CSC properties associated with aggressiveness and metastatic spread.⁷⁵ Krishnamurthy et al.⁷⁶ observed that endothelial cell–secreted factors promoted self-renewal of CSC in head and neck squamous cell carcinomas (HNSCC), as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared with controls. Tang et al.⁷⁷ demonstrated enhanced IL-8 secretion in liver CSCs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. Reinhard et al.⁷⁸ pointed out that ECM molecules and their complementary receptors, such as glycoprotein tenascin-C, the chondroitin sulfate proteoglycan DSD-1-PG/phosphacan, influence the behavior of neural stem cells (NSCs) and CSCs.

Conclusion

Without specific surface markers, GCSC cannot be isolated purely, which may bias research findings. Self-renewal is a marker specific of CSC, which may represent an approach to isolate GCSC. Thus, more detailed research should be conducted to identify the characteristics of GCSC self-renewal.

In summary, a number of pathways and factors are involved in the regulation of GCSC self-renewal, including Wnt, Notch, SHH, Hippo-YAP, TGF-β/Smad, and NF-κB signaling, as well as microenvironment and TFs. However, a holistic understanding of the regulation of GCSC self-renewal is still lacking, but likely involves a complex network system, with several signaling pathways and a variety of cytokines. Through understanding the signaling pathways, microenvironment and TFs in GCSCs self-renewal may lead to the development of novel therapeutic strategies that prevent tumor progression, induce differentiation and apoptosis, and thereby eradicate GCSC populations and contribute to the cure of gastric cancer.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This study was funded by Natural Science Foundation of China (grant number 31471341).

Informed consent

Informed consent was obtained from all individual participants included in the study.

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The self-renewal signaling pathways utilized by gastric cancer stem cells

Abstract

Keywords

Introduction

GCSCs

Identification of GCSCs

Origin of GCSCs

GCSC markers

Self-renewal signaling pathways utilized by GCSCs

Wnt signaling

Sonic hedgehog signaling pathway

Transforming growth factor-β/Smad signaling pathway

Hippo-YAP signaling pathway

Nuclear factor kappa B signaling pathway

Notch signaling pathway

TFs

Microenvironment

Conclusion

Footnotes

Declaration of conflicting interests

Funding

Informed consent

References