RESUMO
Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.
Assuntos
Doenças Autoimunes , Gastrite Atrófica , Tumores Neuroendócrinos , Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Celulas Tipo Enterocromafim/metabolismo , Celulas Tipo Enterocromafim/patologia , Tumores Neuroendócrinos/patologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Gastrite Atrófica/diagnóstico , Gastrite Atrófica/metabolismo , Gastrite Atrófica/patologia , Neoplasias Gástricas/patologia , Lesões Pré-Cancerosas/patologia , Metaplasia/patologia , Mucosa Gástrica/patologiaRESUMO
BACKGROUND: Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. AIM: To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. METHODS: Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. RESULTS: Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. CONCLUSION: Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.
Assuntos
Celulas Tipo Enterocromafim/metabolismo , Gastrinas/sangue , Infecções por Helicobacter/terapia , Helicobacter pylori/isolamento & purificação , Inibidores da Bomba de Prótons/uso terapêutico , Bombas de Próton/metabolismo , Gastropatias/induzido quimicamente , Estudos de Casos e Controles , Celulas Tipo Enterocromafim/efeitos dos fármacos , Gastrinas/fisiologia , Infecções por Helicobacter/diagnóstico , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Estômago , Gastropatias/sangueRESUMO
Studies on the regulation of gastric acid secretion started more than 100 years ago at an early phase of experimental physiology. In nearly the whole last century there were disputes about the interpretation of the findings: the interaction between the three principle gastric acid secretagogues acetylcholine, gastrin and histamine, the cell producing the relevant histamine which turned out to be the ECL cell, the ability of the ECL cell to divide and thus develop into tumours, the classification of gastric carcinomas and the mechanism for Helicobacter pylori carcinogenesis. The elucidation of the central role of the ECL cell and thus its main regulator, gastrin, solve all these controversies, and gives a solid base for handling upper gastrointestinal diseases.
Assuntos
Celulas Tipo Enterocromafim/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Carcinogênese , Celulas Tipo Enterocromafim/patologia , Mucosa Gástrica/patologia , Helicobacter pylori , Humanos , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND/AIMS: Although gastric atrophy is primarily caused by Helicobacter pylori infection, it is unclear why patients serologically diagnosed with gastric atrophy without H. pylori infection exhibit greater atrophy. We investigated histopathological features in serologically diagnosed gastric atrophy without H. pylori infection. METHODS: Thirty-four patients with positive serum pepsinogen and negative serum H. pylori antibody tests underwent gastric biopsy and histological evaluation. The presence of enterochromaffin-like cells (ECL) was also evaluated. Gastric cancer risks for each histological feature according to the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM) were assessed. RESULTS: Twenty-five (74%) patients had histological gastric atrophy. Among those, the following histological subgroups were identified: eight had H. pylori but no ECL, 13 had neither H. pylori nor ECL, and 4 had ECL without H. pylori. Nine patients without histological atrophy had neither H. pylori nor ECL. Patients with H. pylori on histological diagnosis had significantly higher scores on OLGA and OLGIM. CONCLUSIONS: Various histological features, with significant differences in gastric cancer risk, were identified in the gastric mucosa serologically diagnosed with atrophy without H. pylori infection. Therefore, serological screening for gastric cancer risk tests has several limitations, and additional evaluations should be considered.
Assuntos
Celulas Tipo Enterocromafim/metabolismo , Mucosa Gástrica/patologia , Gastrite Atrófica/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Biópsia , Detecção Precoce de Câncer , Feminino , Gastrite Atrófica/diagnóstico , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Neoplasias Gástricas/patologiaRESUMO
ABSTRACT Background: Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. Aim: To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. Methods: Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. Results: Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. Conclusion: Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.
RESUMO Racional: A inibição ácida pelo uso crônico de inibidores de bomba de prótons e o possível aumento da gastrina podem ser seguidos de alterações na regulação da produção do ácido clorídrico. Ainda não está definido se o uso crônico altera a quantidade de células G, D e ECL no estômago ou a razão células G/D. Objetivo: Avaliar o número de células G - produtoras de gastrina -, células D - produtoras de somatostatina - e células ECL - produtoras de histamina -, em pacientes com uso crônico de inibidores de bomba de prótons, com ou sem infecção pelo Helicobacter pylori. Método: Trata-se de estudo retrospectivo avaliando 105 pacientes, 81 usadores crônicos de inibidores de bomba de prótons e 24 controles, através de biópsias com contagem das células G, D e ECL por estudo imunoistoquímico, de forma quantitativa onde havia maior número de células positivas por campo microscópico de grande aumento e em 10 glândulas. Resultados: Não houve diferença estatística comparando-se o número de células G, D e ECL. A razão entre as células G e D foi maior nos pacientes usadores crônicos de inibidores de bomba de prótons. Conclusão: O uso crônico de inibidores de prótons parece não interferir na contagem das células G, D e ECL, porém, interfere na razão entre as células G e D.
Assuntos
Humanos , Gastropatias/induzido quimicamente , Gastrinas/sangue , Helicobacter pylori/isolamento & purificação , Infecções por Helicobacter/terapia , Bombas de Próton/metabolismo , Celulas Tipo Enterocromafim/metabolismo , Inibidores da Bomba de Prótons/uso terapêutico , Estômago , Gastropatias/sangue , Gastrinas/fisiologia , Estudos de Casos e Controles , Infecções por Helicobacter/diagnóstico , Celulas Tipo Enterocromafim/efeitos dos fármacos , Inibidores da Bomba de Prótons/efeitos adversosRESUMO
Gastric cancer, a disease with a reduced frequency for decades, now appears to be on the rise again in young Americans. The epidemiology of gastric cancer differs between tumors in the cardia and those of the more distal parts of the stomach. The tumors are divided into the intestinal type showing glandular growth pattern and the diffuse type with a different pattern. The latter often expresses neuroendocrine and more specifically ECL-cell markers suggesting that they originate from the ECL cell, the target cell for the antral hormone, gastrin. Helicobacter pylori gastritis is accepted as the major cause of gastric cancer, but only after having induced oxyntic atrophy which reduces gastric acid secretion and thus induces hypoacidity leading to hypergastrinemia. Long-term hypergastrinemia is known to induce malignant neoplasia in the stomach of animals as well as man. Recently treatment with proton pump inhibitor after Helicobacter pylori eradication in patients with gastroesophageal reflux disease, has been reported to predispose to gastric cancer. Since profound acid inhibition is a well-known cause of gastric neoplasia, it is to be expected that Helicobacter pylori infection and profound acid inhibition has an additive or possibly potentiating effect on the development of gastric cancer.
Assuntos
Gastrinas/sangue , Gastrite/microbiologia , Refluxo Gastroesofágico/patologia , Infecções por Helicobacter/patologia , Neoplasias Gástricas/patologia , Animais , Celulas Tipo Enterocromafim/metabolismo , Celulas Tipo Enterocromafim/patologia , Refluxo Gastroesofágico/tratamento farmacológico , Helicobacter pylori/patogenicidade , Humanos , Inibidores da Bomba de Prótons/farmacologia , Neoplasias Gástricas/classificaçãoRESUMO
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.
Assuntos
Celulas Tipo Enterocromafim/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Acetilcolina/metabolismo , Animais , Celulas Tipo Enterocromafim/patologia , Mucosa Gástrica/patologia , Histamina/metabolismo , Humanos , Receptor de Colecistocinina B/metabolismoRESUMO
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 A2B 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.
Assuntos
Adenosina Desaminase/genética , Celulas Tipo Enterocromafim/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/metabolismo , Expressão Gênica , Receptor A2B de Adenosina/genética , Adenosina Desaminase/metabolismo , Animais , Biomarcadores , Citometria de Fluxo , Coelhos , Receptor A2B de Adenosina/metabolismoRESUMO
OBJECTIVE: Gastric carcinoids (neuroendocrine tumors) arise from enterochromaffin-like cells in the gastric mucosa. Most are caused by hypergastrinemia. The objectives were to determine if their prevalence in Europe, USA and Japan meets the criteria for an orphan disease and to justify treatment with a gastrin/CCK2 receptor antagonist. METHODS: We obtained data from European and USA cancer registries, and searched PubMed. RESULTS: Prevalence per 10,000 population obtained from cancer registries was: median 0.32 (range 0.09-0.92) for Europe; and 0.17 for the USA, equivalent to 4812 for the whole population. A PubMed search for gastric carcinoids yielded prevalence for Japan only, which was 0.05 per 10,000 population, equivalent to 665 for the entire population. A further search for gastric carcinoids in patients with pernicious anemia (PA) or autoimmune chronic atrophic gastritis (CAG), two presentations of about 80% of gastric carcinoids, produced prevalence rates of 5.2-11%. Prevalence of PA itself was 0.12-1.9%. Data on CAG epidemiology were sparse. CONCLUSION: Prevalence of gastric carcinoids varied widely. All sources probably underestimate prevalence. However, prevalence was below the limits required for recognition by drug regulatory authorities as an orphan disease: 5 per 10,000 population of Europe; 200,000 for the whole population of the USA; and 50,000 for the whole population of Japan. Because gastric carcinoids are an orphan disease, and nonclinical and healthy volunteer studies support treatment with netazepide, a gastrin/CCK2 antagonist, netazepide has been designated an orphan medicinal product in Europe and the USA for development as targeted treatment for gastric carcinoids.
Assuntos
Benzodiazepinonas/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/epidemiologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/epidemiologia , Compostos de Fenilureia/uso terapêutico , Receptor de Colecistocinina B/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Anemia Perniciosa/epidemiologia , Celulas Tipo Enterocromafim/metabolismo , Europa (Continente)/epidemiologia , Feminino , Mucosa Gástrica/metabolismo , Gastrite Atrófica/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Prevalência , Doenças Raras , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
AIMS: To assess synaptophysin expression in columnar-lined oesophageal mucosa showing either goblet cells, known as intestinal metaplasia, or with accompanying oxyntic glands or pyloric glands. METHODS AND RESULTS: Of 159 biopsies, 53 were oesophageal (19 had intestinal metaplasia, 13 oxyntic glands, and 21 pyloric glands), 77 gastric (12 had goblet cells and 27 no goblet cells) and 29 duodenal. Synaptophysin-positive goblet cells were found in all biopsies from the normal duodenum, in 53% of the oesophageal biopsies showing intestinal metaplasia, but only in 8% of gastric biopsies showing intestinal metaplasia. Synaptophysin-positive Paneth cells occurred in all duodenal biopsies, and in nine of the gastric biopsies showing intestinal metaplasia, but in only one of the oesophageal biopsies showing intestinal metaplasia. A continuous synaptophysin-positive neck cell zone was found in all biopsies from the normal antrum, but in none of the oesophageal biopsies with pyloric glands or with chronic antritis. CONCLUSIONS: The paucity or absence of synaptophysin-positive cells in all three phenotypes of Barrett's mucosa might mirror a sequela of chronic inflammation caused by the particular pathogenic bacteria present in the immediate oesophageal microenvironment.
Assuntos
Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Sinaptofisina/metabolismo , Esôfago de Barrett/etiologia , Duodeno/metabolismo , Duodeno/patologia , Celulas Tipo Enterocromafim/metabolismo , Celulas Tipo Enterocromafim/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Metaplasia , Celulas de Paneth/metabolismo , Celulas de Paneth/patologia , Células Parietais Gástricas/metabolismo , Células Parietais Gástricas/patologiaRESUMO
The stomach is innervated by the vagal nerve. Several studies have demonstrated that the vagal nerve has a trophic effect on the rat oxyntic mucosa and that the trophic effect of hypergastrinemia is dependent on intact vagal innervation. The effect of vagal denervation on gastric carcinogenesis has been examined in Mastomys natalensis and hypergastrinemic transgenic INS-GAS mice, with no effect of unilateral vagotomy in Mastomys but an anti-carcinogenic effect in INS-GAS mice. A proportion of female Japanese cotton rats develop spontaneous hypergastrinemia and ECL cell derived gastric carcinomas. In the current study we have examined the effects of unilateral anterior subdiaphragmatic vagotomy on gastric carcinogenesis. Female Japanese cotton rats were operated with unilateral anterior vagotomy or sham-operation at age 2 months and were terminated at age 10 months. Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. When comparing the anterior and posterior sides of the stomachs, vagotomy did not affect the occurrence of dysplasia or carcinoma development in the oxyntic mucosa. However, vagotomy resulted in lower stomach weight and reduced oxyntic mucosal thickness on the anterior side. Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa. In conclusion, vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.
Assuntos
Carcinogênese/patologia , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgia , Neoplasias Gástricas/patologia , Animais , Cromogranina A/metabolismo , Modelos Animais de Doenças , Celulas Tipo Enterocromafim/metabolismo , Feminino , Mucosa Gástrica/inervação , Gastrinas/sangue , Concentração de Íons de Hidrogênio , Sigmodontinae , Vagotomia TroncularRESUMO
BACKGROUND: Sustained acid inhibition with PPI stimulates gastrin secretion, exerting a proliferative drive on enterochromaffin-like cells (ECL cells) of the oxyntic mucosa. It may also accelerate development of gastric gland atrophy in Helicobacter pylori-infected individuals. AIMS: To evaluate gastric exocrine and endocrine cell changes in GERD patients randomised to laparoscopic antireflux surgery (LARS, n = 288) or long-term (5 years) esomeprazole (ESO) treatment (n = 266). METHODS: Antral and corpus biopsies were taken at endoscopy and serum gastrin and chromogranin A levels were assayed, at baseline and after 1, 3 and 5 years' therapy. RESULTS: Biopsies were available at each time point for 158 LARS patients and 180 ESO patients. In H. pylori-infected subjects, antral mucosal inflammation and activity improved significantly (P < 0.001) and stabilised after 3 years on esomeprazole while no change in inflammation was observed after LARS. Oxyntic mucosal inflammation and activity remained stable on esomeprazole but decreased slightly over time after LARS. Neither intestinal metaplasia nor atrophy developed in the oxyntic mucosa. ECL cell density increased significantly after ESO (P < 0.001), corresponding with an increase in circulating gastrin and chromogranin A. After LARS, there was a significant decrease in ECL cell density (P < 0.05), accompanied by a marginal decrease in gastrin and chromogranin. CONCLUSIONS: Antral gastritis improved in H. pylori-infected GERD patients after 5 years on esomeprazole, with little change in laparoscopic antireflux surgery patients, who acted as a control. Despite a continued proliferative drive on enterochromaffin-like cells during esomeprazole treatment, no dysplastic or neoplastic lesions were found and no safety concerns were raised. NCT 00251927.
Assuntos
Antiulcerosos/uso terapêutico , Celulas Tipo Enterocromafim/patologia , Esomeprazol/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Inibidores da Bomba de Prótons/uso terapêutico , Adolescente , Adulto , Idoso , Cromogranina A/sangue , Celulas Tipo Enterocromafim/metabolismo , Feminino , Seguimentos , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Gastrinas/sangue , Refluxo Gastroesofágico/complicações , Infecções por Helicobacter/complicações , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemAssuntos
Tumores Neuroendócrinos/patologia , Neoplasias Gástricas/patologia , Antiulcerosos/farmacologia , Biomarcadores Tumorais/análise , Cromogranina A/análise , Progressão da Doença , Celulas Tipo Enterocromafim/química , Celulas Tipo Enterocromafim/metabolismo , Celulas Tipo Enterocromafim/ultraestrutura , Feminino , Mucosa Gástrica/química , Mucosa Gástrica/patologia , Gastrinas/sangue , Gastrinas/metabolismo , Gastrite Atrófica/patologia , Liberação de Histamina , Humanos , Hiperplasia , Metaplasia , Pessoa de Meia-Idade , Tumores Neuroendócrinos/química , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/cirurgia , Células Parietais Gástricas/efeitos dos fármacos , Células Parietais Gástricas/metabolismo , Neoplasias Gástricas/química , Neoplasias Gástricas/cirurgia , Sinaptofisina , Proteínas de Transporte Vesicular/análiseRESUMO
Gastrin, acting through peripheral cholecystokinin (CCK) 2 receptors, is a major hormonal regulator of gastric acid secretion. The effects of gastrin on acid secretion occur both acutely and chronically because gastrin directly stimulates gastric acid secretion and also exerts trophic effects on the enterochromaffin-like and parietal cells that together constitute the acid secretory apparatus of the stomach. Several antagonists that target the CCK2 receptor have been identified and investigated for the treatment of gastroesophageal reflux disease and pancreatic cancer. In this paper, we discuss the contribution of gastrin to these disease pathologies and the data generated to date from clinical studies investigating CCK2 receptor antagonists.
Assuntos
Sistemas de Liberação de Medicamentos , Gastrinas/metabolismo , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Celulas Tipo Enterocromafim/metabolismo , Ácido Gástrico/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/patologia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Células Parietais Gástricas/metabolismo , Receptor de Colecistocinina B/metabolismoRESUMO
Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-G(R) cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-G(R) cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.
Assuntos
Células Epiteliais/metabolismo , Gastrinas/farmacologia , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Celulas Tipo Enterocromafim/metabolismo , Gastrinas/sangue , Humanos , Octreotida , RNA Mensageiro/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Estômago/citologia , Ativador de Plasminogênio Tipo Uroquinase/biossínteseRESUMO
Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1â cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.
Assuntos
Adenocarcinoma/metabolismo , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Neoplasias Gastrointestinais/metabolismo , Fator de Crescimento Insulin-Like I/biossíntese , Tumores Neuroendócrinos/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Celulas Tipo Enterocromafim/metabolismo , Feminino , Neoplasias Gastrointestinais/patologia , Humanos , Imuno-Histoquímica , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Estatísticas não ParamétricasRESUMO
BACKGROUND: Gastrectomy may disturb the body's mineral homeostasis, with osteopenia and osteoporosis being among the late outcomes. Parathyroid hormone-like hormone (PTHLH) was detected in rat gastric enterochromaffin-like (ECL) cells in 2005, and some researchers suggested that it was the hypothetical hormone gastrocalcin that is believed to lead to osteoporosis. AIMS: Our objective was to learn whether PTHLH is expressed in human gastric ECL cells and to form a basic understanding about the relationship between PTHLH and gastrin. METHODS: We collected normal human gastric mucosa specimens and serum samples from 28 patients. RESULTS: RT-PCR and immunohistochemical analysis demonstrated weak expression of PTHLH in ECL cells at the RNA and protein levels. A low level of PTHLH expression was also found in the serum. Serum gastrin did have a significant positive correlation with the relative ratio of PTHLH mRNA to ß-actin levels in gastric mucosa (rs=0.569, p=0.002). CONCLUSIONS: This indicates that PTHLH has a low signal expression in human gastric ECL cells and that serum gastrin levels correlate with PTHLH RNA levels in gastric mucosa. Further work is needed to evaluate the functional role of PTHLH in ECL cells and to determine whether PTHLH is gastrocalcin.
Assuntos
Celulas Tipo Enterocromafim/metabolismo , Gastrinas/sangue , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/sangue , Actinas/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gastropatias/cirurgiaAssuntos
Dispepsia/etiologia , Celulas Tipo Enterocromafim/metabolismo , Ácido Gástrico/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Colite Isquêmica/epidemiologia , Pólipos do Colo/complicações , Doença de Crohn/diagnóstico , Refluxo Gastroesofágico/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Intestino Delgado/patologia , Pancreatopatias/diagnóstico por imagem , Fatores de Risco , UltrassonografiaRESUMO
OBJECTIVE: The recent description of dyspepsia in healthy individuals after stopping treatment with proton-pump inhibitors (PPIs) indicates that reflux disease may worsen due to this treatment. The aim of this paper is to review current knowledge of the regulation of gastric acid secretion, including maximal acid secretion, and to improve understanding of the pathogenesis of acid-related conditions. MATERIAL AND METHODS: We reviewed our findings from three decades of studies on gastric acid secretion in the isolated rat stomach and in humans as well as studies by the group of Robert Jensen involving gastrinoma patients. RESULTS: The parietal cell has receptors for histamine and acetylcholine, whereas the gastrin receptor is localized to the enterochromaffin-like (ECL) cell. Gastrin-stimulated histamine release depends on the ECL cell mass, which is regulated by gastrin. The parietal cell mass is also influenced by gastrin. All conditions with hypergastrinemia concomitant with a normal oxyntic mucosa result in an increase in acid secretion. Helicobacter pylori infection in the antral mucosa may induce duodenal ulcers by its effect on acid secretion, as in patients with gastrinoma. Whereas PPIs induce clinically important rebound acid hypersecretion, histamine-2 blockers do not, since they also induce tolerance. CONCLUSION: From a biological and physiological point of view, patients should be given treatment that disturbs the normal physiology as little as possible.
Assuntos
Dispepsia/etiologia , Celulas Tipo Enterocromafim/metabolismo , Ácido Gástrico/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Animais , Gastrinoma/metabolismo , Refluxo Gastroesofágico/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Histamina/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Células Parietais Gástricas/metabolismo , Ratos , Neoplasias Gástricas/metabolismoRESUMO
The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.