Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Barrett's esophagus, a squamous-to-columnar cell metaplasia that develops as a result of chronic gastroesophageal reflux disease (GERD), is a risk factor for esophageal adenocarcinoma. The molecular events underlying the pathogenesis of Barrett's metaplasia are poorly understood, but recent studies suggest that interactions among developmental signaling pathways, morphogenetic factors, and Caudal homeobox (Cdx) genes play key roles. Strong expression of Cdx genes normally is found in the intestine but not in the esophagus and stomach. When mice are genetically engineered so that their gastric cells express Cdx, the stomach develops a metaplastic, intestinal-type epithelium similar to that of Barrett's esophagus. Exposure to acid and bile has been shown to activate the Cdx promoter in certain esophageal cell lines, and Cdx expression has been found in inflamed esophageal squamous epithelium and in the specialized intestinal metaplasia of Barrett's esophagus. Barrett's metaplasia must be sustained by stem cells, which might be identified by putative, intestinal stem cell markers like leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and doublecortin and CaM kinase-like-1 (DCAMKL-1). Emerging concepts in tumor biology suggest that Barrett's cancers may develop from growth-promoting mutations in metaplastic stem cells or their progenitor cell progeny. This report reviews the roles of developmental signaling pathways and the Cdx genes in the development of normal gut epithelia and the potential mechanisms whereby GERD may induce the esophageal expression of Cdx genes and other morphogenetic factors that mediate the development of Barrett's metaplasia. The role of stem cells in the development of metaplasia and in carcinogenesis and the potential for therapies directed at those stem cells also is addressed.
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PMID:Acid, bile, and CDX: the ABCs of making Barrett's metaplasia. 1855 17

The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and Barrett esophagus, a squamous-to-columnar cell metaplasia that predisposes to malignancy. Adenocarcinomas in Barrett esophagus are thought to arise through a sequence of growth-promoting, genetic alterations that accumulate until the cells have acquired the physiologic hallmarks of cancer proposed by Hanahan and Weinberg. Moreover, GERD and Barrett esophagus are associated with chronic esophagitis, and inflammation is a well known risk factor for cancer formation. The cell that gives rise to Barrett metaplasia is not known. It has been proposed that the metaplasia may arise from a change in the differentiation pattern of stem cells that either reside in the esophagus or are recruited to the esophagus from the bone marrow. Alternatively, it is possible that Barrett metaplasia develops through the conversion of one differentiated cell type into another. Regardless of the cell of origin, Barrett metaplasia ultimately must be sustained by stem cells, which might be identified by intestinal stem cell markers. An emerging concept in tumor biology is that cancer stem cells are responsible for sustaining tumor growth. If Barrett cancers develop from Barrett stem cells, then a therapy targeted at those stem cells might prevent esophageal adenocarcinoma. This report reviews the risk factors for Barrett esophagus and esophageal adenocarcinoma, the mechanisms by which genetic alterations might contribute to carcinogenesis in Barrett esophagus, and the role of stem cells in the development of Barrett metaplasia and adenocarcinoma.
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PMID:Esophageal adenocarcinoma arising in Barrett esophagus. 1870 77

Squamous intraepithelial lesions (SILs) of the larynx, clinically usually defined as leukoplakia and chronic laryngitis, have remained the main controversial topic in laryngeal pathology for decades as regards classification, histological diagnosis and treatment. SILs are caused by smoking and alcohol abuse. There is also mounting evidence that gastroesophageal reflux is a potential aetiological factor. Human papillomavirus infection seems to play little if any role in laryngeal carcinogenesis. Histological classification of SILs is the central disputed aspect of these lesions. There are as yet no generally accepted criteria for histological grading of laryngeal SILs. Three currently used classifications of SILs are reviewed here: the dysplasia system, the Ljubljana classification and the binary system of squamous intraepithelial neoplasia. One of the most important issues of SILs is the risk of malignant transformation. Data in the literature are controversial because of inconsistent use of morphological criteria in different classifications. It is often difficult for clinicians to agree on the most appropriate therapeutic option for a particular grade of SIL that has been diagnosed. Transition from normal epithelium to SILs and squamous cell carcinoma is related to progressive accumulation of genetic changes leading to a clonal population of transformed epithelial cells. Despite extensive research into these genetic changes in laryngeal carcinogenesis, reliable genetic markers with diagnostic and prognostic value are still lacking.
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PMID:Current review on squamous intraepithelial lesions of the larynx. 1875 37

Omeprazole is a drug used for treating gastro-oesophageal reflux disease and duodenal ulcers. Omeprazole induces a xenobiotic-metabolizing enzyme, cytochrome P450 1A1 (CYP1A1), as its ligand by aryl hydrocarbon receptor (AhR) activation without binding. CYP1A1-inducible chemicals, such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, are known to have adverse effects (i.e. carcinogenesis, mutagenesis and malformation). Unlike these typical AhR activators, omeprazole has shown no experimental evidence of carcinogenic activity. The possibility, however, remains that omeprazole may aggravate the effect of environmental carcinogens through CYP1A1 induction. We exposed benzo[a]pyrene and omeprazole simultaneously to human and mouse hepatoma cells to investigate the synergistic effect of these chemicals. Contrary to our prediction, cytotoxicity of benzo[a]pyrene was inhibited by the omeprazole exposure in a dose-dependent manner. Omeprazole did not alter CYP1A1 mRNA and protein levels induced by benzo[a]pyrene. The 7-ethoxy-resorufin-O-deethylase assay revealed that omeprazole inhibited CYP1A1 enzyme activity. Kinetic analysis also demonstrated that it is a competitive inhibitor for CYP1A1. The K(m) value of omeprazole against CYP1A1 activity was 50.1 microM. We conclude that the effects of omeprazole on CYP1A1 involve not only induction through AhR activation but also inhibition of its enzyme activity, and that the protective effect of omeprazole against benzo[a]pyrene cytotoxicity depends on the latter.
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PMID:Omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. 1879 72

Informative and tractable animal models that are colonized by well-defined microbial pathogens represent ideal systems for the study of complex human diseases. Helicobacter pylori colonization of the stomach is a strong risk factor for peptic ulceration and distal gastric cancer. However, gastritis has no adverse consequences for most hosts and emerging evidence suggests that H. pylori prevalence is inversely related to gastroesophageal reflux disease and allergic disorders. These observations indicate that eradication may not be appropriate for certain populations due to the potentially beneficial effects conferred by persistent gastric inflammation. Animal models have provided an invaluable resource with which to study H. pylori pathogenesis and carcinogenesis, and have permitted the development of a focused approach to selectively target human populations at high-risk of disease.
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PMID:Helicobacter pylori infection and disease: from humans to animal models. 1904 53

Esophageal cancer is a significant worldwide health problem because of its poor prognosis and high incidence in certain parts of the world. Tobacco smoke and alcohol consumption are significant risk factors for esophageal squamous cell carcinoma, whereas frequent gastroesophageal reflux and subsequent inflammatory reactions play a role in causing the adenocarcinoma. Esophageal carcinogenesis involves multiple genetic alterations. A large body of knowledge has been generated regarding molecular alterations associated with esophageal carcinogenesis. These alterations include aberrant cell cycle control, DNA repair, cellular enzymes, growth factor receptors, and nuclear receptors. This chapter reviews the most frequent gene alterations and their correlation with risk factors as well as the prevention strategies in esophageal cancer.
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PMID:Risk factors and gene expression in esophageal cancer. 1910 88

Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 microm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFkappaB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFkappaB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.
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PMID:Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells. 1915 54

Gastroesophageal reflux disease (GERD) is a major risk factor for the development of esophageal adenocarcinoma (ACE). Many molecular alterations occur in esophageal carcinogenesis, yet the exact mechanism of ACE development remains unknown. This study aims to determine p53 protein and Ki-67 expression in esophageal mucosa of patients with GERD and study the correlation between these markers and the progression from normal squamous epithelium to esophagitis, columnar epithelium with or without intestinal metaplasia and ACE. We analyzed p53 protein and Ki-67 expression in biopsies of 200 patients with GERD and 35 patients with ACE. Those biopsies were classified into five groups: (i) G1 normal squamous epithelium (58); (ii) G2 esophagitis (80); (iii) G3 columnar epitheliums without intestinal metaplasia (30); (iv) G4, columnar epitheliums with intestinal metaplasia (32); and (v) G5 ACEs (35). p53 protein overexpression was found in 7% (4) of G1, 37.5% (30) of G2, 30% (9) of G3, 62.5% (20) of G4, and 71.4% (25) of G5 (p < 0.001). Ki-67 index increased according to the severity of histopathological diagnoses. Ki67 index was 21.3 +/- 19.5% in G1, 38.8 +/- 24.9% in G2, 37.7 +/- 26.3% in G3, 52.8 +/- 24.6% in G4, and 57.1 +/- 25.1% in G5 (P < 0.001). Linear correlation between p53/Ki67 expression and the multistep progression from squamous epithelium to ACE was observed (P < 0.001 and P < 0.05). Our results indicate that overexpression of p53 and increased Ki-67 could be associated with the development and progression to ACE in patients with GERD.
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PMID:P53 and Ki-67 overexpression in gastroesophageal reflux disease--Barrett's esophagus and adenocarcinoma sequence. 1930 8

The incidence of esophageal adenocarcinoma is increasing largely in Western populations, and patients diagnosed with this cancer continue to have a poor prognosis. The major risk factors are gastroesophageal reflux disease and Barrett's esophagus, both of which are associated with inflammation of the esophageal squamous epithelium, a condition called reflux esophagitis. The cellular mechanisms contributing to cancer development in the esophagus are poorly understood. The chronic inflammation that is present in Barrett's esophagus creates an environment suitable for DNA damage and altered expression of genes involved in cellular proliferation and inhibition of apoptosis. Key players in the inflammatory cascade include generation of free radicals, activation of kinases pathways and transcription factors, and production of cytokines and inflammatory enzymes. The current review highlights the link between reflux-induced inflammation and esophageal carcinogenesis. Understanding the molecular pathways involved in inflammation-associated esophageal tumorigenesis could enable the development of targeted therapies and offer a better therapeutic treatment in esophageal cancer.
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PMID:Inflammation and esophageal carcinogenesis. 1959 8

Esophageal atresia (EA) is a rather common neonatal anomaly frequently associated with other congenital anomalies such as cardiac, genitourinary, and anorectal malformations and chromosomal disorders. It is suggested that the abnormal pattern of expression of the gene Sonic hedgehog is associated with failure of tracheoesophageal separation resulting in EA in an animal model. EA with distal tracheoesophageal fistula (TEF) is the most common type of EA and is usually treated successfully with division of the TEF and primary anastomosis. However, the optimal surgical treatment for long-gap EA remains controversial. Even though the results of delayed anastomosis with the Lividitis method or Collis-Nissen method are mainly reported to be satisfactory, long-term results show a high incidence of gastroesophageal reflux (GER) and esophageal dysmotility. Replacement with the gastric tube, stomach, colon, or jejunum has been performed when the gap is too long to use the native esophagus. Anastomotic stricture, obstruction due to redundancy, and adhesion of substitutes were reported in long-term follow-up studies. Moreover, the risk of carcinogenesis in Barrett's metaplasia, which is associated with GER, must be taken into consideration. Thus, long-term follow-up into adulthood is warranted in patients with EA.
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PMID:[Long-term complications of esophageal atresia]. 1966 31


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