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Barrett's metaplasia
- The molecular basis of transdifferentiation

Barrett's metaplasia

Barrett's metaplasia is a pathological condition characterised by a phenotypic switch in oesophageal epithelium from stratified squamous to intestinal type columnar epithelium containing mucin-secreting goblet cells [68]. This switch predisposes to oesophageal adenocarcinoma [69], the incidence of which has increased rapidly in the last three decades [70] and carries a poor prognosis with a 5-year mortality exceeding 80% [71]. The development of Barrett's oesophagus is related to reflux of gastro-duodenal contents, with an annual rate of progression to adenocarcinoma of approximately 0.5% [72]. The neoplastic change follows a metaplasiadysplasia- carcinoma sequence, with dysplasia classified into low grade or high grade depending on the severity of atypical cytological alterations and nuclear polymorphism. The histological assessment of dysplasia and prediction of cancer risk is subjective and hampered by inter-observer variability [73]. There has been considerable interest in using somatic mutations such as aneuploidy, p53 mutations, cyclin D1 overexpression, decreased E-cadherin expression and APC inactivation as markers to predict neoplastic progression [reviewed in 74]. By contrast, the molecular events prompting the initial metaplastic switch from stratified squamous to intestinal type columnar epithelium are at present poorly understood.

Role of cdx2 in Barrett's metaplasia

Recently, there has been interest in the homeodomain transcription factor cdx2 as an early marker of Barrett's metaplasia. cdx2 is located on chromosome 13 in humans and is a member of the Parahox cluster [75]. Various recent results suggest that cdx2 is a master switch gene whose expression normally distinguishes between the upper and lower regions of alimentary canal epithelia. First, it is normally expressed in the postgastric epithelium during embryonic development and into adult life [76, 77]. Second, ectopic expression in the stomach can provoke intestinal metaplasia. Silberg and colleagues directed ectopic cdx2 expression to the stomach in transgenic mice using cis-regulatory elements of the foxa3 promoter [78]. The induction of intestinal metaplasia was confirmed both histologically and by demonstrating intestine-specific genes within the gastric mucosa. Mutoh and colleagues used the H+/K+ ATPase β-subunit gene promoter in a transgenic mouse to drive gastric cdx2 expression and similarly demonstrated intestinal metaplasia [79]. As discussed by Beck, the proton pump functions postnatally and cdx2 may therefore have been expressed in differentiated gastric epithelium [80]. This raises the question of whether there has been a transdifferentiation to intestinal type epithelium or whether a subset of parietal cells retain progenitor potential. Evidence for the master switch function of cdx2 is further supported by loss of function in the intestine leading to transformations to squamous epithelium resembling the oesophagus and forestomach. This is seen in focal colonic lesions of cdx2 +/- mice within which cdx2 expression has been completely lost [81]. Interestingly, ectopic squamous patches in the colon are bordered by regions of gastric and small intestinal type epithelium [82]. The appearance of 'intermediate' tissue types is ascribed to intercalary regeneration, which occurs at a junction between experimentally joined body parts resulting in the formation of parts which normally lie between them [1], and may reflect a gradient in developmental commitment between the focus of forestomach and surrounding colonic epithelium. Faller and colleagues demonstrated that gastric metaplasia in the duodenum was associated with loss of cdx2 expression and its target gene product sucraseisomaltase [83]. These observations together suggest that cdx2 directs intestinal development towards a caudal phenotype and that the 'default' state resembles forestomach epithelium. cdx2 has been demonstrated in Barrett's metaplasia, oesophagitis and intestinal metaplasia of the stomach in humans [84–87]. Moons and colleagues demonstrated cdx2 mRNA in the squamous epithelium above the Barrett's segment in one third of patients and speculate that its expression may precede the switch in phenotype [87]. There is mounting evidence that cdx2 may be involved in the transition from squamous epithelium to intestinal columnar epithelium in Barrett's metaplasia. Whether this is a causative effect or merely an association remains to be elucidated. The situation is further complicated by the recent report by Mutoh and colleagues using a transgenic mouse with ectopic cdx1 expression in the stomach under the H+/K+ ATPase β-subunit gene promoter which provoked similar, although not identical, intestinal metaplasia to their transgenic cdx2 mouse model [88]. The molecular events in the development of Barrett's metaplasia may therefore be controlled by one, or a small number, of master switch genes. The exact mechanism of action of these transcription factors remains to be clarified.

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