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Gland-associated H pylori induce Lgr5 þ stem cell-derived hyperproliferation and hyperplasia. (A) Confocal cross sections of antral glands from either uninfected (uninf) or 2-month H pylori-infected (2 mo) Lgr5-eGFP-IRES-CreERT2/ Rosa26-TdTomato mice. Lineage tracing (red) was induced 5 days before harvesting. (B) Scatter plot quantifying the lineage tracing ratio of individual glands from uninfected vs 2-month infected animals. (C) Antral glands stained with H&E from uninfected vs 2-month infected animals. (D) Antral inflammation and hyperplasia scores from uninfected vs 2-month infected animals. (E) Longitudinal section through the entire antrum of an Lgr5-eGFP-IRES-CreERT2/ Rosa26-TdTomato mouse infected for 2 months with H pylori. Gland-associated bacteria from the boxed area are magnified in the right panel. Lineage tracing (red) was induced 5 days before harvesting. Total gland height (line), gland tracing height (red), and number of bacteria per gland (green) are mapped below according to location. The scatter plot correlates the gland tracing height to the density of gland-associated H pylori combining data from 3 different animals. Results of Spearman correlation test are shown. Scale bar ¼ 100 mm.
Source publication
Helicobacter pylori infection is the main risk factor for gastric cancer. We characterized the interactions of H pylori with gastric epithelial progenitor and stem cells in humans and mice and investigated how these interactions contribute to H pylori-induced pathology.
We used quantitative confocal microscopy and 3-dimensional reconstruction of en...
Contexts in source publication
Context 1
... hyperplastic responses occur in areas of the stomach where glands are colonized (Supplementary Figure 3), and because we observed that H pylori stably colonize and interact with progenitor and stem cells, we asked whether H pylori infection locally affects the turnover of antral Lgr5 þ stem cells and their progeny. 17 To compare the turnover rates in individual antral glands, we used the lineage tracing technique to mark cells print & web 4C=FPO Figure 1. ...
Context 2
... imaged the antrum by confocal microscopy and measured the length of tracing in each gland labeled with TdTomato. We found that after 2 months of H pylori infection, lineage tracing in the antral glands is significantly accelerated compared with glands in uninfected mice ( Figure 3A and B). Histologic examination also revealed that infection induced hyperplasia and chronic inflammation in the antrum ( Figure 3C and D). ...
Context 3
... found that after 2 months of H pylori infection, lineage tracing in the antral glands is significantly accelerated compared with glands in uninfected mice ( Figure 3A and B). Histologic examination also revealed that infection induced hyperplasia and chronic inflammation in the antrum ( Figure 3C and D). Because the distribution of H pylori in the antral glands is not homogeneous throughout the stomach, we tested whether direct gland colonization correlates with localized stem cell activation. ...
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... then mapped the location and quantity of the bacteria in individual glands and correlated bacterial density per gland with the lineage tracing length ( Figure 3E). The map- ping analysis of the antral tissue revealed a significant cor- relation between the number of bacteria in individual glands and the height of lineage tracing of the glands (P < .0001; ...
Context 5
... map- ping analysis of the antral tissue revealed a significant cor- relation between the number of bacteria in individual glands and the height of lineage tracing of the glands (P < .0001; r ¼ 0.67; Figure 3E, Supplementary Figure 7A). Our data shows that gland-associated H pylori induce local changes in gland turnover, which results in gland hyperplasia. ...
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... mapped the tracing height and bacterial numbers in the antral glands of DCagE-infected animals ( Figure 6E). We found a weaker correlation between bacterial burden in infected glands and tracing height in DCagE-infected animals as compared with WT ( Figure 6E vs Figure 3E, and Supplementary Figure 7; Pearson correlation of 0.19 vs 0.67, respectively). These data suggest that the cag TFSS and CagA contribute to the hyperproliferative responses that are locally induced by gland-associated bacteria. ...
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Citations
... Poor colonization by the PMSS1 strain may account for some of the poor inflammation. Sigal et al. found that HP PMSS1 is present in the antrum but does not colonize the gastric corpus glands of C57BL/6J mice 2 months post-challenge (49). Moreover, interactions with the microbiota may abrogate HP-induced inflammation as the same study reported that C57BL/6 mice from different vendors exhibit dramatic differences in corpus inflammation (49). ...
... Sigal et al. found that HP PMSS1 is present in the antrum but does not colonize the gastric corpus glands of C57BL/6J mice 2 months post-challenge (49). Moreover, interactions with the microbiota may abrogate HP-induced inflammation as the same study reported that C57BL/6 mice from different vendors exhibit dramatic differences in corpus inflammation (49). It is important to note that HP colonization patterns vary significantly by strain. ...
Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis.
IMPORTANCE
Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.
... Recent research has revealed the existence of gastric cancer stem cells (GCSCs) and elimination of GCSCs could be focused on targeting cell surface markers that are essential for maintaining stemness properties [43]. Many CSC markers, such as CD133 [44], CD44 [45], CD24 [46], CD54 [47], CD90 [48], EpCAM [49], and LGR5 [50], have been employed to identify GCSCs. Among them, CD133 and CD44 are currently the most used cell surface markers [51]. ...
Background
Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6‐methyladenosine (m ⁶ A)‐binding protein involved in a variety of cancers. However, whether m ⁶ A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance.
Methods
The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry.
Results
Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug‐resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5‐fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m ⁶ A‐dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β‐catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non‐responders compared with responders.
Conclusion
Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β‐catenin pathway and exacerbate chemoresistance in GC.
... LGR5 was also present in normal stem cells which governs tissue homeostasis. Potentially these LGR5-positive cells are amenable to oncogenic transformation (89). The positive results of LGR5 expression in cancer are related to its basal level in different organs. ...
Leucine-rich G protein-coupled receptor 5 (LGR5) is a marker of cancer stem cells (CSCs) in various cancers. Based on different studies, conflicting reports exist on correlation between LGR5 expression and poor prognosis/ clinicopathological parameters in cancer patients. Therefore, our purpose in conducting this study was to investigate correlation between LGR5 expression and outcomes of cancer patients under study through a systematic review and meta-analysis. Relevant articles were searched and collected using EMBASE, PubMed, Science Direct, and Scopus databases until December 21, 2022. This study was conducted to examine correlation between LGR5 expression and different clinical outcomes, such as recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), and clinicopathological characteristics of the included cancer patients. To achieve this, hazard ratios (HRs) with 95% confidence intervals (CIs) and odds ratios (ORs) with 95% CIs were used as statistical measures. A meta-analysis was conducted using STATA 12.0 software. Finally, 53 studies including 9523 patients met the inclusion criteria. Significantly, high-level expression of LGR5 was related to poor prognosis in terms of OS, higher tumor stage, presence of distant metastasis, and presence of lymph node metastasis. It was discovered through subgroup analysis that several factors, including the study area, evaluation method, and type of cancer, can influence the correlation between LGR5 expression and negative prognosis in cancer patients. According to the results of our study, LGR5 overexpression was related to poor OS in cancer patients. In addition, clinicopathological data indicated an unfavorable prognosis in cancer patients with high LGR5 expression. In conclusion, LGR5 may serve as a potential prognostic marker for predicting survival in certain cancer types.
... While we recapitulated the preference for pit cells in our murine organoid model, we additionally detected H. pylori bound to Lgr5 + stem and progenitor cells in antral cultures and to Troy + stem and progenitor cells in corpus cultures. This observation is in line with the ability of H. pylori to colonize not only the surface epithelium but also the depth of both murine and human gastric glands, where the bacteria can be found in close proximity to Lgr5 + cells in murine antrum and to mitotic progenitor cells in human antrum and corpus (45,46). This interaction with Lgr5 + cells leads to their T4SS-dependent expansion (hyperplasia) and to the induction of antimicrobial factors (45). ...
... This observation is in line with the ability of H. pylori to colonize not only the surface epithelium but also the depth of both murine and human gastric glands, where the bacteria can be found in close proximity to Lgr5 + cells in murine antrum and to mitotic progenitor cells in human antrum and corpus (45,46). This interaction with Lgr5 + cells leads to their T4SS-dependent expansion (hyperplasia) and to the induction of antimicrobial factors (45). Lgr5 + cells mount a robust, R-spondin-3-driven antimicrobial response to H. pylori in vivo, which results in clearance (or at least a reduction) of the bacteria and presumably serves to protect the gland base and its stem cell pool (41). ...
... Gland base stem cells are the primary cell lineage responding to H. pylori and its ADP-heptose with the production of proinflammatory mediators; this has been definitively shown for antrum stem cells (47) and possibly also applies to corpus basal stem cells. The expansion of Lgr5 + gland base stem cells is not only observed in infected mice (45) but also observed in human carriers of H. pylori (48). These various observations are very well in line with our observation that DNA damage induced by H. pylori in organoid cells preferentially affects Lgr5 + / Troy + stem and progenitor cells and is dependent on both active transcription and replication. ...
Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori –induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)–positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.
... pylori), a class I carcinogen [29,30], particularly in East Asian countries [31,32], and chronic H. pylori infection affects nearly half the world's population [33]. H. pylori or H. felis infection induces gastric chronic inflammation while enhancing gastric stemness [34,35]; moreover, these infections upregulate PPARδ to promote gastric epithelial proliferation in mice and humans [8,36], indicating that PPARδ plays an important role in H. pylori infectionrelated GAC . ...
Background
Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ–mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms.
Methods
The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter–driven PPARδ overexpression ( Ppard TG ). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in Ppard TG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay.
Results
GSK3787 significantly suppressed GAC carcinogenesis in Ppard TG mice. PPARδ increased Ccl20 level to chemoattract Ccr6 ⁺ immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8 ⁺ T cells in gastric tissues. GSK3787 suppressed PPARδ–induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of Ppard TG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice.
Conclusions
PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.
... Aside from biofilm growth on abiotic surfaces, additional studies have also suggested that H. pylori can form a microcolony network that adhered and grew between epithelial cell junctions on human cells [27,28] and in murine gastric glands [29]. Mature H. pylori biofilms consist of different cell shapes within one multicellular population. ...
Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori’s chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, shifted morphology, modulated metabolism, efflux pumps, and virulence factors. Recent developments in therapeutic approaches targeting H. pylori biofilm have shown that synthetic compounds, such as small molecule drugs and plant-derived compounds, are effective at eradicating H. pylori biofilms. These combined topics highlight the necessity for biofilm-based research in H. pylori, to improve current H. pylori-targeted therapeutic approaches and alleviate relative public health burden. In this review we discuss recent discoveries that have decoded the life cycle of H. pylori biofilms and current biofilm-targeted treatment strategies.
... Together with the work by Böttcher et al. (73), our present study raises the intriguing possibility that CagA-mediated perturbation of Wnt/ PCP signaling at the base of the gastric pyloric glands, where Lgr5 + stem cells reside, hampers polarity cue dependent switching of the stem cell niche signal from the canonical to the noncanonical Wnt/PCP signal and thereby dampens cell fate determination, which allows excess proliferation of stem/progenitor cells in the absence of cell-lineage specification, such as maturation into enteroendocrine cells (Fig. 8B). Consistent with this idea, Sigal et al. (75) showed that H. pylori directly interacts with LGR5 + stem cells at the gastric pyloric glands and expands them in a CagA-dependent manner. The LGR5 + stem cell expansion may involve CagA-mediated Wnt/PCP signal perturbation, which could be further enhanced by canonical Wnt/β-catenin signaling that is stimulated by interaction of CagA with E-cadherin and glycogen synthase kinase 3β (GSK3β) (76, 77). ...
Helicobacter pylori strains that deliver the oncoprotein CagA into gastric epithelial cells are the major etiologic agents of upper gastric diseases including gastric cancer. CagA promotes gastric carcinogenesis through interactions with multiple host proteins. Here, we show that CagA also disrupts Wnt-dependent planar cell polarity (Wnt/PCP), which orients cells within the plane of an epithelium and coordinates collective cell behaviors such as convergent extension to enable epithelial elongation during development. Ectopic expression of CagA in Xenopus laevis embryos impaired gastrulation, neural tube formation, and axis elongation, processes driven by convergent extension movements that depend on the Wnt/PCP pathway. Mice specifically expressing CagA in the stomach epithelium had longer pyloric glands and mislocalization of the tetraspanin proteins VANGL1 and VANGL2 (VANGL1/2), which are critical components of Wnt/PCP signaling. The increased pyloric gland length was due to hyperproliferation of cells at the gland base, where Lgr5+ stem and progenitor cells reside, and was associated with fewer differentiated enteroendocrine cells. In cultured human gastric epithelial cells, the N terminus of CagA interacted with the C-terminal cytoplasmic tails of VANGL1/2, which impaired Wnt/PCP signaling by inducing the mislocalization of VANGL1/2 from the plasma membrane to the cytoplasm. Thus, CagA may contribute to the development of gastric cancer by subverting a Wnt/PCP-dependent mechanism that restrains pyloric gland stem cell proliferation and promotes enteroendocrine differentiation.
... Our data confirm previous well-established links between H. pylori and gastric disorders, which are based on bacterial lifelong persistence in the human gastric mucosa of approximately 50% of the world's population (18)(19)(20)(21). Using a potent flagellar system and chemotactic receptors, H. pylori can penetrate the mucus and colonize gastric epithelial cells in the pit and deep in gastric glands (20,22,23). ...
... Our data confirm previous well-established links between H. pylori and gastric disorders, which are based on bacterial lifelong persistence in the human gastric mucosa of approximately 50% of the world's population (18)(19)(20)(21). Using a potent flagellar system and chemotactic receptors, H. pylori can penetrate the mucus and colonize gastric epithelial cells in the pit and deep in gastric glands (20,22,23). Recent studies have revealed the interplay between bacterium and host epithelium, demonstrating key mechanisms in activation of stem cells leading to hyperplasia and a robust and sustained innate and adaptive immune response that fails to clear H. pylori, rather supporting a chronic inflammatory condition, laying ground for cancer initiation and progression (20,(24)(25)(26)(27)(28)(29). ...
... Using a potent flagellar system and chemotactic receptors, H. pylori can penetrate the mucus and colonize gastric epithelial cells in the pit and deep in gastric glands (20,22,23). Recent studies have revealed the interplay between bacterium and host epithelium, demonstrating key mechanisms in activation of stem cells leading to hyperplasia and a robust and sustained innate and adaptive immune response that fails to clear H. pylori, rather supporting a chronic inflammatory condition, laying ground for cancer initiation and progression (20,(24)(25)(26)(27)(28)(29). In addition to being linked to gastritis and gastroduodenal ulcers, our data confirm an association between H. pylori positivity and IDA. ...
Background:
Helicobacter pylori colonizes the human stomach. Infection causes chronic gastritis and increases the risk for gastroduodenal ulcer and gastric cancer. Its chronic colonization in the stomach triggers aberrant epithelial and inflammatory signals, that are also associated with systemic alterations.
Methods:
Using PheWAS analysis in more than 8.000 participants in the community-based UK Biobank we explored the association of H. pylori positivity with gastric and extra gastric disease and mortality in a European country.
Results:
Along with well-established gastric diseases we dominantly found overrepresented cardiovascular, respiratory, and metabolic disorders. Using multivariate analysis, the overall mortality of H. pylori positive participants was not altered, while the respiratory and COVID-19 associated mortality increased. Lipidomic analysis for H. pylori positive participants revealed a dyslipidemic profile with reduced HDL cholesterol and omega-3 fatty acids, which may represent a causative link between infection, systemic inflammation, and disease.
Conclusion:
Our study of H. pylori positivity demonstrates that it plays an organ- and disease entity-specific role in the development of human disease and highlight the importance of further research into the systemic effects of H. pylori infection.
... Besides increasing cancer cell "stemness," F. nucleatum directly targets CR-CSCs via multiple interactions (CbpF/CEACAM1; Fap2-Gal/GalNac); F. nucleatum infection further increases the constitutively high Wnt activity of CSCs, while eliciting resistance to cell death and NF-kB-dependent chemokine release (see below 5.2) [68]. Likewise, H. Pylori directly activates Lgr5+ gastric stem and progenitor cells, leading to gland hyperplasia and remodeling [149], changes eventually conducive to malignant transformation. ...
Simple Summary
Colorectal cancer is one of the most frequently diagnosed and deadly malignancies worldwide, but our understanding of why this life-threatening disease occurs is still limited. With trillions of bacteria inhabiting our intestines, especially the large intestine, where cancer most frequently develops, it is no surprise that gut microbes have been under scrutiny. One of the prime suspect microorganisms is Fusobacterium nucleatum, an oral pathogen believed to lodge in colon cancer at its initial stage and foster its progression to full malignancy. Based on a review of the available information, we propose that Fusobacterium facilitates colorectal cancer through a misguided attempt to heal the diseased mucosa gone tragically wrong. This provocative view aims at stimulating discussion and putting the healing wound-cancer analogy in the spotlight of future research on the role of gut bacteria in colon malignancy.
Abstract
Adult stem cells lie at the crossroads of tissue repair, inflammation, and malignancy. Intestinal microbiota and microbe–host interactions are pivotal to maintaining gut homeostasis and response to injury, and participate in colorectal carcinogenesis. Yet, limited knowledge is available on whether and how bacteria directly crosstalk with intestinal stem cells (ISC), particularly cancerous stem-like cells (CR-CSC), as engines for colorectal cancer initiation, maintenance, and metastatic dissemination. Among several bacterial species alleged to initiate or promote colorectal cancer (CRC), the pathobiont Fusobacterium Nucleatum has recently drawn significant attention for its epidemiologic association and mechanistic linkage with the disease. We will therefore focus on current evidence for an F. nucleatum-CRCSC axis in tumor development, highlighting the commonalities and differences between F. nucleatum-associated colorectal carcinogenesis and gastric cancer driven by Helicobacter Pylori. We will explore the diverse facets of the bacteria–CSC interaction, analyzing the signals and pathways whereby bacteria either confer “stemness” properties to tumor cells or primarily target stem-like elements within the heterogeneous tumor cell populations. We will also discuss the extent to which CR-CSC cells are competent for innate immune responses and participate in establishing a tumor-promoting microenvironment. Finally, by capitalizing on the expanding knowledge of how the microbiota and ISC crosstalk in intestinal homeostasis and response to injury, we will speculate on the possibility that CRC arises as an aberrant repair response promoted by pathogenic bacteria upon direct stimulation of intestinal stem cells.
... We have used GFP-labeled H. pylori Hp0547 to trace the infection stage to search the entering pathways. In general, it has been reported that H. pylori directly colonizes into the surface of gastric cancer stem cells and adheres to gastric mucosa epithelial cells, and then attaches to superficial cell pits [25,26]. We found that the GFP signal of GFP-labeled H. pylori 0547 was present in the organoids for at least one week after injection. ...
... LGR5+ stem cells in the base of the antrum glands drive the repopulation of the glands by giving rise to highly proliferative progenitor cells. These progenitor cells, located in the mid-glandular compartment, rapidly divide, and differentiate into all epithelial lineages [25]. The amino acid polymorphism of H. pylori CagL-like Y58E59 was associated with a higher risk of gastric cancer and may regulate a corpus shift of gastric integrin α5β1, leading to severe corpus gastritis during gastric carcinogenesis [18,22]. ...
We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.
