Search Results (11)

The gastric endocrine population comprises functionally distinct cell types that exhibit both neuronal and endocrine characteristics; however, their molecular markers remain incompletely defined. Here, we identify growth differentiation factor 9 (GDF9), nephrin (NPHS1), and rearranged during transfection (RET) as novel markers of gastric endocrine cells. A co-immunofluorescence (IF) analysis demonstrated that GDF9, NPHS1, and RET are co-expressed with chromogranin A (CHGA), a well-known marker of gastrointestinal endocrine cells. Further Co-IF analysis revealed that GDF9-expressing cells were negative for ghrelin and somatostatin, whereas NPHS1 was co-expressed with both hormones. A subpopulation of RET-positive cells co-expressed ghrelin but not somatostatin. Notably, GDF9- and RET-positive cells co-expressed dopamine decarboxylase (DDC), consistent with enrichment in enterochromaffin-like (ECL) cells. Revisitation of our previous mRNA-sequencing data revealed reduced transcript levels of Gdf9, Nphs1, and Ret in CA-PKA mice, which express constitutively active protein kinase A (PKA) and develop gastric preneoplastic lesions. Co-IF and cellular quantification showed a localized reduction in the density of GDF9 and CHGA-positive endocrine cells, together with altered abundance of NPHS1- and RET-expressing cells in CA-PKA stomachs. These changes occurred in the context of extensive hyperplasia of the surrounding epithelium, indicating that the observed alterations reflect localized reduction and non-cell-autonomous effects of epithelial expansion. Notably, we observed RET misexpression outside the endocrine compartment in CA-PKA mice, suggesting that aberrant RET signaling may contribute to lesions by promoting abnormal glandular branching. Together, these findings identify GDF9, NPHS1, and RET as novel markers of gastric endocrine cells and their potential role in gastric homeostasis. Full article

Background/Objectives: Autoimmune metaplastic atrophic gastritis (AMAG) is a chronic, autoimmune-mediated condition associated with increased risk of malignancy and nutritional deficiencies, yet diagnostic and follow-up processes remain inconsistent and unclear. This study investigates follow-up testing performance in patients with AMAG and neuroendocrine tumors (NET), as well as the correlation between endoscopic impressions and histologic findings. Methods: We retrospectively analyzed 65 gastric biopsies with final diagnoses or comments mentioning the possibility of AMAG, 12 of which included well-differentiated WHO grade 1 NET arising in AMAG. H&E slides were reviewed to assess atrophy severity, the presence or absence of enterochromaffin-like (ECL) cell hyperplasia, and Helicobacter organisms. The final diagnostic line or comments made were scored from 1 to 5, based on the strength of the language used to alert the treating clinician to the likelihood of AMAG. Corresponding endoscopy reports were scored from 1 to 5 based on the likelihood of the reports documenting AMAG features. Data regarding follow-up laboratory testing relevant to AMAG and biopsy performance were collected from the electronic medical records. Results: Endoscopy scores showed no significant associations with the histology comment score or atrophy grade. The histology comment score was positively associated with performing at least a total of three laboratory tests (p = 0.03). No association was found between the presence or absence of follow-up biopsy and histology comment score (p = 0.60). Follow-up biopsy was more common in patients with NET than those with AMAG without NET (p < 0.001). Conclusions: Poor endoscopic–histologic correlation with variable follow-up practices highlights the need for standardized protocols in AMAG management. Enhanced adherence to biopsy guidelines, standardized pathology reporting, and consistent surveillance, particularly for patients with AMAG without NET, are imperative to improve diagnosis and outcomes. Future research should focus on optimizing endoscopic techniques, standardizing serological tests, and establishing evidence-based surveillance protocols for AMAG patients. Full article

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately leading to pernicious anemia. Compensatory hypergastrinemia promotes enterochromaffin-like (ECL) cell hyperplasia and contributes to the development of type 1 gastric neuroendocrine neoplasms (gNENs). These clinical consequences are well recognized, yet the cellular and molecular mechanisms driving mucosal atrophy and neoplastic transformation remain incompletely defined. Recent advances highlight the role of endoplasmic reticulum stress, impaired autophagy, innate immune effectors, and dysbiosis in perpetuating inflammation and epithelial injury. The frequent coexistence of AIG with other autoimmune disorders further adds to its clinical complexity. Therapeutic options remain limited, spanning vitamin B12 replacement and endoscopic management to emerging targeted approaches. Netazepide, a gastrin/CCK2 receptor antagonist, is the only agent tested in clinical trials, whereas interventions targeting ER stress, autophagy, immune tolerance, or microbiome composition are still in the preclinical stage. Clarifying these mechanisms is crucial to improve biomarker development, optimize surveillance, and identify targeted therapies to prevent neoplastic transformation. Full article

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management. Full article

Malignant tumors are a consequence of genetic changes mainly occurring during cell division, sometimes with a congenital component. Therefore, accelerated cell divisions will necessarily predispose individuals, whether due to conditions of chronic cell destruction or hormonal overstimulation. It has been postulated that two genetic hits are necessary for the development of malignancy (Knudson). The correct view is probably that the number of genetic changes needed depends on the role the mutated genes have in proliferation and growth control. Hormones should accordingly be regarded as complete carcinogens. In this review based upon experience of gastric cancer where gastrin is central in the pathogenesis, it is argued that oxyntic atrophy—and not metaplasia as postulated by Correa—is the central precancer change in gastric mucosa. Moreover, the target cell of gastrin, the enterochromaffin-like (ECL) cell, is central in gastric carcinogenesis and most probably the cell of origin of gastric carcinomas of the diffuse type according to Lauren (a classification probable in accordance with biology). The distinction between adenocarcinomas and neuroendocrine carcinomas based upon a certain percentage of cancer cells with neuroendocrine differentiation is questioned. To make progress in the treatment of cancer, a correct classification system and knowledge of the pathogenesis are necessary. Full article

The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer. Full article

Cancers are believed to originate from stem cells. Previously, the hypothesis was that tumors developed due to dedifferentiation of mature cells. We studied the regulation of gastric acid secretion and showed that gastrin through the gastrin receptor stimulates enterochromaffin-like (ECL) cell histamine release and proliferation. In animal and human studies, we and others showed that long-term hypergastrinemia results in ECL cell-derived tumor through a sequence of hyperplasia, dysplasia, neuroendocrine tumors (NETs), and possibly neuroendocrine carcinomas (NECs) and adenocarcinomas of diffuse type. Perhaps, other cancers may also have their origin in differentiated cells. Knowledge of the growth regulation of the cell of origin is important in cancer prophylaxis and treatment. Physiology plays a central role in carcinogenesis through hormones and other growth factors. Every cell division implies a small risk of mutation; thus mitogens are also mutagens. Moreover, metastasis of slow proliferating cells may also explain so-called tumor dormancy and late recurrence. Full article

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin’s effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects. Full article

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use. Full article

Background: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. Methods: This review is based upon literature research and personal knowledge. Results: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. Conclusions: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion. Full article

Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal cells through A_2B adenosine receptor (A2BR) binding. A functional link between surface A2BR and adenosine deaminase (ADA) was found in parietal cells, but whether this connection is a general feature of gastric mucosa cells is unknown. Here we examine whether A2BR is expressed at the membrane of histamine-producing enterochromaffin-like (ECL) cells, the major endocrine cell type in the oxyntic mucosa, and if so, whether it has a vicinity relationship with ADA. We used a highly homogeneous population of rabbit ECL cells (size 7.5–10 µm) after purification by elutriation centrifugation. The surface expression of A2BR and ADA proteins was assessed by flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are partially coexpressed at the gastric ECL cell surface and that A2BR is functional, with regard to binding of adenosine analogs and adenylate cyclase activation. The physiological relevance of A2BR and ADA association in regulating histamine release is yet to be explained. Full article