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Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa
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Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 28106

Special Issue Editors

Dr. Francesco Boccellato

E-Mail Website
Guest Editor
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
Interests: stem cells; 3D cultures; epithelium; regeneration; infection; carcinogenesis
Prof. Dr. Werner Hoffmann

E-Mail Website
Guest Editor
Director of the Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
Interests: protection, regeneration and repair of mucous epithelia with special emphasis on the role of TFF peptides; TFF peptides in the immune and central nervous systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is gathering high-quality original manuscripts and reviews that look into the molecular and cellular determinants contributing to the changes observed in the gastric mucosa during carcinogenesis. Although the stages of the gastric pre-cancerous cascade have been well characterized, the molecular forces driving this sequential tissue alteration are still poorly understood. It is also widely accepted that Helicobacter pylori infection is the main risk factor in gastric carcinogenesis. However the molecular and cellular causality linking the infection to cellular transformation are currently under investigation. This Special Issue aims to bring together experts in stem cells, immunology, genomic and microbiology to study the regulation of tissue homeostasis and mechanisms of cellular transformation in the stomach.

Dr. Francesco Boccellato
Prof. Dr. Werner Hoffmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Gastric mucosa
  • Homeostasis
  • Infection
  • Epithelium
  • Stem cells
  • Carcinogenesis
  • Helicobacter pylori
  • Host response to infection
  • Mutations
  • Regeneration
  • Gastritis
  • Atrophy
  • Metaplasia
  • Reprogramming
  • DNA damage
  • Methylation
  • Epigenetics.

Published Papers (7 papers)

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Research

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11 pages, 3918 KiB  
Article
JAK-STAT1 Signaling Pathway Is an Early Response to Helicobacter pylori Infection and Contributes to Immune Escape and Gastric Carcinogenesis
by Xue Li, Kaifeng Pan, Michael Vieth, Markus Gerhard, Wenqing Li and Raquel Mejías-Luque
Int. J. Mol. Sci. 2022, 23(8), 4147; https://doi.org/10.3390/ijms23084147 - 08 Apr 2022
Cited by 18 | Viewed by 2746
Abstract
Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune [...] Read more.
Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04–5.30)). We observed that STAT1 was activated in human H. pylori-positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori, we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori-induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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13 pages, 3132 KiB  
Article
Mouse Gastric Epithelial Cells Resist CagA Delivery by the Helicobacter pylori Type IV Secretion System
by Rejina Shrestha, Naoko Murata-Kamiya, Satoshi Imai, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura and Masanori Hatakeyama
Int. J. Mol. Sci. 2022, 23(5), 2492; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052492 - 24 Feb 2022
Cited by 6 | Viewed by 2212
Abstract
The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is [...] Read more.
The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ–Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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Review

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23 pages, 2467 KiB  
Review
Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor
by Werner Hoffmann
Int. J. Mol. Sci. 2022, 23(10), 5377; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105377 - 11 May 2022
Cited by 4 | Viewed by 4483
Abstract
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is [...] Read more.
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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20 pages, 1343 KiB  
Review
Morphogen Signals Shaping the Gastric Glands in Health and Disease
by Claudia Zagami, Diana Papp, Alice Anna Daddi and Francesco Boccellato
Int. J. Mol. Sci. 2022, 23(7), 3632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073632 - 26 Mar 2022
Cited by 2 | Viewed by 6101
Abstract
The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. [...] Read more.
The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. Cells at different positions in the gland sense a specific combination of signals that instruct them to differentiate, proliferate, regenerate, or migrate. Differentiated cells perform specific functions involved in digestion, such as the production of protective mucus and the secretion of digestive enzymes or gastric acid. Biopsies from gastric precancerous conditions usually display tissue aberrations and change the shape of the glands. Alteration of the morphogen signalling microenvironment is likely to underlie those conditions. Furthermore, genes involved in morphogen signalling pathways are found to be frequently mutated in gastric cancer. We summarise the most recent findings regarding alterations of morphogen signalling during gastric carcinogenesis, and we highlight the new stem cell technologies that are improving our understanding of the regulation of human tissue shape. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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17 pages, 1185 KiB  
Review
Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer
by Sulaimon Idowu, Paul P. Bertrand and Anna K. Walduck
Int. J. Mol. Sci. 2022, 23(5), 2790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052790 - 03 Mar 2022
Cited by 4 | Viewed by 4141
Abstract
Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human [...] Read more.
Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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18 pages, 6631 KiB  
Review
Proteolytic Landscapes in Gastric Pathology and Cancerogenesis
by Sabine Bernegger, Miroslaw Jarzab, Silja Wessler and Gernot Posselt
Int. J. Mol. Sci. 2022, 23(5), 2419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052419 - 22 Feb 2022
Cited by 5 | Viewed by 3177
Abstract
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events [...] Read more.
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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17 pages, 722 KiB  
Review
Matrix Metalloproteinases in Helicobacter pylori–Associated Gastritis and Gastric Cancer
by Olga Sokolova and Michael Naumann
Int. J. Mol. Sci. 2022, 23(3), 1883; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031883 - 08 Feb 2022
Cited by 18 | Viewed by 3998
Abstract
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric [...] Read more.
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori–associated gastritis and gastric cancer. Full article
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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