RESUMEN
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
RESUMEN
Background: Spasmolytic polypeptide expression metaplasia (SPEM) occurs in the corpus of the stomach and is closely related to inflammations caused by H. pylori infection. Recently, SPEM was suggested as one of the dubious precancerous lesions of gastric cancer (GC). Thus, further research on SPEM cell transdifferentiation and its underlying mechanisms could facilitate the development of new molecular targets improving the therapeutics of GC. Using bibliometrics, we analyzed publications, summarized the research hotspots and provided references for scientific researchers engaged in related research fields. Methods: We searched the Web of Science Core Collection (WoSCC) for publications related to SPEM-GC from 2002 to 2022. The VOSviewer, SCImago, CiteSpace and R software were used to visualize and analyze the data. Gene targets identified in the keyword list were analyzed for functional enrichment using the KEGG and GO databases. Results: Of the 292 articles identified in the initial search, we observed a stable trend in SPEM-GC research but rapid growth in the number of citations. The United States was the leader in terms of quality publications and international cooperation among them. The total number of articles published by Chinese scholars was second to the United States. Additionally, despite its low centrality and average citation frequency, China has become one of the world's most dynamic countries in academics. In terms of productivity, Vanderbilt University was identified as the most productive institution. Further, we also observed that Gastroenterology was the highest co-cited journal, and Goldenring Jr. was the most prolific author with the largest centrality. Conclusion: SPEM could serve as an initial step in diagnosing gastric precancerous lesions. Current hotspots and frontiers of research include SPEM cell lineage differentiation, interaction with H. pylori, disturbances of the mucosal microenvironment, biomarkers, clinical diagnosis and outcomes of SPEM, as well as the development of proliferative SPEM animal models. However, further research and collaboration are still required. The findings presented in this study can be used as reference for the research status of SPEM-GC and determine new directions for future studies.
Asunto(s)
Lesiones Precancerosas , Neoplasias Gástricas , Animales , Bibliometría , Carcinogénesis , Metaplasia , Péptidos/genética , Lesiones Precancerosas/patología , Neoplasias Gástricas/patología , Microambiente Tumoral , HumanosRESUMEN
Differentiated cells have evolved paligenosis, a conserved program to return to a stem or progenitor state and reenter the cell cycle to fuel tissue repair. Paligenosis comprises three sequential stages: 1) quenching of MTORC1 activity with induction of massive macroautophagy/autophagy that remodels differentiated cell architecture; 2) induced expression of progenitor/repair-associated genes; 3) MTORC1 reactivation with cell cycle reentry. Here, we summarize work showing that evolutionarily conserved genes - Ddit4 and Ifrd1 - are critical regulators of paligenosis. DDIT4 suppresses MTORC1 function to induce lysosomes and autophagosomes in paligenosis stage 1. As DDIT4 decreases during paligenosis, TRP53 continues MTORC1 suppression until cells are licensed to reenter the cell cycle by IFRD1 suppression of TRP53. Cells with DNA damage maintain TRP53 until either the damage is repaired, or they undergo apoptosis. The concept of paligenosis and identification of paligenosis-dedicated genes may provide new angles to harness tissue regeneration and specifically target tumor cells.
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Apoptosis/fisiología , Autofagosomas/metabolismo , Ciclo Celular/fisiología , Diferenciación Celular/fisiología , Animales , División Celular/fisiología , Proliferación Celular/fisiología , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismoRESUMEN
Pyloric metaplasia (PM) and pseudopyloric metaplasia (PPM) are metaplastic changes resulting in pyloric-type glands in the gastric oxyntic mucosa that mainly occur in chronic gastritis caused by Helicobacter pylori (H. pylori) infection. Focusing on PM and PPM, we classified the histological changes in gastric mucosa according to the Updated Sydney System, using 314 biopsy specimens of gastric greater curvature of the middle body before H. pylori eradication (HPE). Next, the numbers of PM and PPM glands were counted in 47 specimens, and subjects were followed up over 10 years after HPE. PPM was recognized jointly with inflammation, activity, atrophy, and intestinal metaplasia, but PM was recognized more frequently than PPM as atrophy and intestinal metaplasia progressed. Both PM and PPM regressed significantly within 6 years after HPE. Additionally, we demonstrated that PM and PPM are not always coincident with spasmolytic polypeptide-expressing metaplasia (SPEM). In conclusion, PM and PPM are considered different modulations of the same line of differentiation, which are both reversible, with PM potentially emerging from PPM upon progression.
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Mucosa Gástrica/patología , Gastritis/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/patogenicidad , Biopsia , Diferenciación Celular , Enfermedad Crónica , Mucosa Gástrica/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Gastritis/tratamiento farmacológico , Gastritis/metabolismo , Gastritis/microbiología , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Metaplasia , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is present in more than 90% of resected gastric cancer tissues. However, although widely regarded as a pre-cancerous tissue, its genetic characteristics have not been well studied. METHODS: Immunohistochemistry using Trefoil factor 2 (TFF2) antibodies was used to identify TFF2-positive SPEM cells within SPEM glands in the stomach of Helicobacter felis (H. felis) -infected mice and human clinical samples. Laser microdissection was used to isolate specific cells from both the infected mice and the human samples. The genetic instability in these cells was examined by measuring the lengths of microsatellite (MS) markers using capillary electrophoresis. Also, genome-wide genetic variations in the SPEM cells from the clinical sample was examined using deep whole-exome sequencing. RESULTS: SPEM cells indeed exhibit not only heightened MS instability (MSI), but also genetic instabilities that extend genome-wide. Furthermore, surprisingly, we found that morphologically normal, TFF2-negative cells also contain a comparable degree of genomic instabilities as the co-resident SPEM cells within the SPEM glands. CONCLUSION: These results, for the first time, clearly establish elevated genetic instability as a critical property of SPEM glands, which may provide a greater possibility for malignant clone selection. More importantly, these results indicate that SPEM cells may not be the sole origin of carcinogenesis in the stomach and strongly suggest the common progenitor of these cells, the stem cells, as the source of these genetic instabilities, and thus, potential key players in carcinogenesis.
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Péptidos y Proteínas de Señalización Intercelular/genética , Metaplasia/genética , Neoplasias Gástricas/genética , Factor Trefoil-2/genética , Animales , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica/genética , Inestabilidad Genómica/genética , Xenoinjertos , Humanos , Masculino , Metaplasia/patología , Ratones , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Neoplasias Gástricas/patologíaRESUMEN
Chronic inflammation of the gastric mucosa, often caused by autoimmune gastritis and/or infection with Helicobacter pylori, can lead to atrophy of acid-secreting parietal cells with metaplasia of remaining cells. The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation-induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon-γ (IFN-γ), on gastric epithelial cells. IFN-γ was applied to three-dimensional organoid cultures of gastric epithelial cells derived from gastric corpus gland (gastroids) of control and IFN-γ receptor-deficient mice. Gastroids were also treated with supernatants from activated immune cells isolated from a mouse model of autoimmune-mediated atrophic gastritis (TxA23) with and without IFN-γ expression. Finally, histopathological analysis of atrophy and metaplasia severity was performed in TxA23 mice and compared to TxA23 × Ifng-/- mice. Gastric epithelial cells in gastroid cultures expressed IFN-γ receptor in the basolateral membrane, and gastroids died when treated with IFN-γ in an IFN-γ receptor-dependent manner. Supernatants from immune cells containing high levels of IFN-γ were highly toxic to gastroids, and toxicity was tempered when IFN-γ was either neutralized using a monoclonal antibody or when supernatants from Ifng-/- mouse immune cells were used. Finally, TxA23 × Ifng-/- mice showed near-complete abrogation of pre-cancerous histopathological atrophy and metaplasia versus IFN-γ-sufficient controls. We identify IFN-γ as a critical promoter of parietal cell atrophy with metaplasia during the progression of gastritis to gastric atrophy and metaplasia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Mucosa Gástrica/patología , Interferón gamma/fisiología , Neoplasias Gástricas/patología , Animales , Atrofia/patología , Muerte Celular/fisiología , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Células Epiteliales/patología , Gastritis , Interferón gamma/deficiencia , Interferón gamma/farmacología , Metaplasia/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Parietales Gástricas/patología , Células Tumorales CultivadasRESUMEN
Despite a significant decrease in the incidence of gastric cancer in Western countries over the past century, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Most human gastric cancers develop after long-term Helicobacter pylori infection via the Correa pathway: the progression is from gastritis, atrophy, intestinal metaplasia, dysplasia, to cancer. However, it remains unclear whether metaplasia is a direct precursor of gastric cancer or merely a marker of high cancer risk. Here, we review human studies on the relationship between metaplasia and cancer in the stomach, data from mouse models of metaplasia regarding the mechanism of metaplasia development, and the cellular responses induced by H. pylori infection.
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Lesiones Precancerosas/patología , Neoplasias Gástricas/patología , Estómago/patología , Animales , Biomarcadores , Modelos Animales de Enfermedad , Epigénesis Genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Helicobacter pylori , Humanos , Metaplasia , Ratones , Clasificación del Tumor , Transducción de Señal , Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismoRESUMEN
Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians.
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Adenocarcinoma/química , Biomarcadores de Tumor/análisis , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/aislamiento & purificación , Péptidos/análisis , Lesiones Precancerosas/química , Neoplasias Gástricas/química , Estómago/química , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma/virología , Biopsia , Distribución de Chi-Cuadrado , China , Femenino , Gastritis/metabolismo , Gastritis/patología , Gastritis/virología , Herpesvirus Humano 4/genética , Humanos , Inmunohistoquímica , Hibridación in Situ , Péptidos y Proteínas de Señalización Intercelular , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Metaplasia , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Lesiones Precancerosas/patología , Lesiones Precancerosas/cirugía , Lesiones Precancerosas/virología , Modelos de Riesgos Proporcionales , ARN Viral/genética , Estómago/patología , Estómago/virología , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/virologíaRESUMEN
The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach. NEW & NOTEWORTHY: Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem cells induces hyperproliferation and tissue hypertrophy, suggesting that Notch may drive gastric tumorigenesis.
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Proliferación Celular/fisiología , Células Epiteliales/fisiología , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Estómago/fisiología , Animales , Femenino , Mucosa Gástrica/citología , Genes Reporteros , Humanos , Masculino , Ratones , Organoides/citología , Organoides/fisiología , Receptor Notch1/genética , Receptor Notch2/genética , Transducción de Señal/fisiología , Células Madre , Tamoxifeno/farmacologíaRESUMEN
Parietal cell loss represents the initial step in the sequential progression toward gastric adenocarcinoma. In the setting of chronic inflammation, the expansion of the mucosal response to parietal cell loss characterizes a crucial transition en route to gastric dysplasia. Here, we detail methods for using the selective estrogen receptor modulator tamoxifen as a novel tool to rapidly and reversibly induce parietal cell loss in mice in order to study the mechanisms that underlie these pre-neoplastic events.