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1-6 of 6
Keyword: Barrett's oesophagus
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Articles
Biochem Soc Trans (2010) 38 (2): 321-326.
Published: 22 March 2010
...Jianping Kong; Douglas B. Stairs; John P. Lynch Barrett's oesophagus is the replacement of normal squamous oesophageal epithelium with an intestinalized columnar epithelium. Although some insight has been gained as to what Barrett's oesophagus is, how this columnar epithelium emerges from within a...
Abstract
Barrett's oesophagus is the replacement of normal squamous oesophageal epithelium with an intestinalized columnar epithelium. Although some insight has been gained as to what Barrett's oesophagus is, how this columnar epithelium emerges from within a stratified squamous epithelium remains an unanswered question. We have sought to determine whether oesophageal keratinocytes can be trans-differentiated into Barrett's oesophagus cells. Using an Affymetrix microarray, we found unexpectedly that gene-expression patterns in the Barrett's oesophagus were only slightly more similar to the normal small intestine than they were to the normal oesophagus. Thus gene-expression patterns suggest significant molecular similarities remain between Barrett's oesophagus cells and normal squamous oesophageal epithelium, despite their histological resemblance with intestine. We next determined whether directed expression of intestine-specific transcription factors could induce intestinalization of keratinocytes. Retroviral-mediated Cdx2 ( Caudal -type homeobox 2) expression in immortalized human oesophageal keratinocytes engineered with human telomerase reverse transcriptase (EPC2-hTERT cells) could be established transiently, but not maintained, and was associated with a reduction in cell proliferation. Co-expression of cyclin D1 rescued proliferation in the Cdx2-expressing cells, but co-expression of dominant-negative p53 did not. Cdx2 expression in the EPC2-hTERT.D1 cells did not induce intestinalization. However, when combined with treatments that induce chromatin remodelling, there was a significant induction of Barrett's oesophagus-associated genes. Studies are ongoing to determine whether other intestinal transcription factors, either alone or in combination, can provoke greater intestinalization of oesophageal keratinocytes. We conclude that, on the basis of gene-expression patterns, Barrett's oesophagus epithelial cells may represent an intermediate between oesophageal keratinocytes and intestinal epithelial cells. Moreover, our findings suggest that it may be possible to induce Barrett's oesophagus epithelial cells from oesophageal keratinocytes by altering the expression of certain critical genes.
Articles
Biochem Soc Trans (2010) 38 (2): 327-330.
Published: 22 March 2010
... associated with Barrett's oesophagus, although causal mechanisms have not been clearly defined. Recently, obesity and dietary nitric oxide have also been implicated in the disease pathogenesis. We have demonstrated that acid can alter cell kinetics and, together with nitric oxide, can induce double-stranded...
Abstract
Most epithelial cancers occur on the background of chronic exposure to damaging agents which is reflected in the long lag phase from development of a pre-invasive lesion to the development of a carcinoma. Luminal refluxate has long been recognized to be associated with Barrett's oesophagus, although causal mechanisms have not been clearly defined. Recently, obesity and dietary nitric oxide have also been implicated in the disease pathogenesis. We have demonstrated that acid can alter cell kinetics and, together with nitric oxide, can induce double-stranded DNA breaks. Aside from exposure to luminal factors, the stromal micro-environment may also be important. There is increasing evidence to suggest that inflammatory pathways such as TGF (transforming growth factor) β may play a role in Barrett's oesophagus carcinogenesis. Hence stromal–epithelial–luminal interactions may influence cell behaviour. As sequelae to this, it is possible that the niches created by the micro-environment may influence genetic epithelial diversity observed within the Barrett's oesophagus segment.
Articles
Biochem Soc Trans (2010) 38 (2): 331-336.
Published: 22 March 2010
...Kirill Pavlov; Carlo C. Maley Research in Barrett's oesophagus, and neoplastic progression to OAC (oesophageal adenocarcinoma), is hobbled by the lack of good pre-clinical models that capture the evolutionary dynamics of Barrett's cell populations. Current models trade off tractability for realism...
Abstract
Research in Barrett's oesophagus, and neoplastic progression to OAC (oesophageal adenocarcinoma), is hobbled by the lack of good pre-clinical models that capture the evolutionary dynamics of Barrett's cell populations. Current models trade off tractability for realism. Computational models are perhaps the most tractable and can be used both to interpret data and to develop intuitions and hypotheses for neoplastic progression. Tissue culture models include squamous cell lines, Barrett's oesophagus cell lines and OAC cell lines, although it was recognized recently that BIC-1, SEG-1 and TE-7 are not true OAC cell lines. Some of the unrealistic aspects of the micro-environment in two-dimensional tissue culture may be overcome with the development of three-dimensional organotypic cultures of Barrett's oesophagus. The most realistic, but least tractable, model is a canine surgical model that generates reflux and leads to an intestinal metaplasia. Alternatively, rat surgical models have gained popularity and should be tested for the common genetic features of Barrett's oesophagus neoplastic progression in humans including loss of CDKN2A (cyclin-dependent kinase inhibitor 2A) and TP53 (tumour protein 53), generation of aneuploidy and realistic levels of genetic diversity. This last feature will be important for studying the effects of cancer-prevention interventions. In order to study the dynamics of progression and the effects of an experimental intervention, there is a need to follow animals longitudinally, with periodic endoscopic biopsies. This is now possible and represents an exciting opportunity for the future.
Articles
Biochem Soc Trans (2010) 38 (2): 370-373.
Published: 22 March 2010
...Mariagnese Barbera; Rebecca C. Fitzgerald Barrett's oesophagus is a metaplastic pre-malignant disorder and the only established precursor lesion for oesophageal adenocarcinoma. Barrett's oesophagus develops when the normal stratified squamous epithelium of the lower oesophagus is replaced by a...
Abstract
Barrett's oesophagus is a metaplastic pre-malignant disorder and the only established precursor lesion for oesophageal adenocarcinoma. Barrett's oesophagus develops when the normal stratified squamous epithelium of the lower oesophagus is replaced by a columnar lined mucosa with intestinal differentiation, usually in the context of chronic gastro-oesophageal reflux disease. The cellular and molecular mechanisms by which this metaplastic transformation occurs are poorly understood. Abnormal differentiation of multipotent stem cells in the squamous oesophagus, triggered by exposure to refluxate, is one potential mechanism. These stem cells could be located in the basal layer of the squamous oesophageal epithelium and/or in the neck region of the oesophageal submucosal gland ducts; however, their exact location and identification are still matter of discussion. Three-dimensional models combined with state-of-the-art imaging techniques are now applied to characterize the squamous epithelium in human oesophageal samples, and this could unveil essential information to identify these progenitor cells. Locating stem cells in human squamous oesophagus could have important implications for our understanding of Barrett's oesophagus and remarkably improve our future strategies for its prevention.
Articles
Biochem Soc Trans (2010) 38 (2): 343-347.
Published: 22 March 2010
...Qizhi Huang; Laura J. Hardie Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular...
Abstract
Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.
Articles
Biochem Soc Trans (2010) 38 (2): 374-379.
Published: 22 March 2010
...Trevor A. Graham; Stuart A.C. McDonald Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we...
Abstract
Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis.