Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium.

Barrett's metaplasia is the only known morphological precursor to oesophageal adenocarcinoma and is characterized by replacement of stratified squamous epithelium by columnar epithelium. The cell of origin is uncertain and the molecular mechanisms responsible for the change in cellular phenotype are poorly understood. We therefore explored the role of two transcription factors, Cdx2 and HNF4α in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4α. A new organ culture system for adult murine oesophagus is described. Using this, Cdx2 and HNF4α were ectopically expressed by adenoviral infection. The phenotype following infection was determined by a combination of PCR, immunohistochemical and morphological analyses. We demonstrate the expression of CDX2 and HNF4α in human biopsy samples. Our oesophageal organ culture system expressed markers characteristic of the normal SSQE: p63, K14, K4 and loricrin. Ectopic expression of HNF4α, but not of Cdx2 induced expression of Tff3, villin, K8 and E-cadherin. HNF4α is sufficient to induce a columnar-like phenotype in adult mouse oesophageal epithelium and is present in the human condition. These data suggest that induction of HNF4α is a key early step in the formation of Barrett's metaplasia and are consistent with an origin of Barrett's metaplasia from the oesophageal epithelium.

The role of Cdx2 in Barrett's metaplasia.

Metaplasia (or transdifferentiation) is defined as the transformation of one tissue type to another. Clues to the molecular mechanisms that control the development of metaplasia are implied from knowledge of the transcription factors that specify tissue identity during normal embryonic development. Barrett's metaplasia describes the development of a columnar/intestinal phenotype in the squamous oesophageal epithelium and is the major risk factor for oesophageal adenocarcinoma. This particular type of cancer has a rapidly rising incidence and a dismal prognosis. The homoeotic transcription factor Cdx2 (Caudal-type homeobox 2) has been implicated as a master switch gene for intestine and therefore for Barrett's metaplasia. Normally, Cdx2 expression is restricted to the epithelium of the small and large intestine. Loss of Cdx2 function, or conditional deletion in the intestine, results in replacement of intestinal cells with a stratified squamous phenotype. In addition, Cdx2 is sufficient to provoke intestinal metaplasia in the stomach. In the present paper, we review the evidence for the role of Cdx2 in the development of Barrett's metaplasia.

Barrett's metaplasia: molecular mechanisms and nutritional influences.

Barrett's metaplasia is discussed in the context of a general theory for the formation of metaplasias based on developmental biology. The phenotype of a particular tissue type becomes established during embryonic development by the expression of a specific set of transcription factors. If this combination becomes altered, then the tissue type can be altered. Such events may occur by mutation or by environmental effects on gene expression, normally within the stem cell population of the tissue. A macroscopic patch of metaplastic tissue will arise only if the new gene activity state is self-sustaining in the absence of its original causes, and if the new tissue type can outgrow the parent tissue type. An important candidate gene for the causation of Barrett's metaplasia is Cdx2 (Caudal-type homeobox 2). In normal development, this is expressed in the future intestine, but not the future foregut. Mouse knockout studies have shown that it is needed for intestinal development, and that its loss from adult intestine can lead to squamous transformations. It is also expressed in Barrett's metaplasia and can be activated in oesophageal cell cultures by treatment with bile acids. We have investigated the ability of Cdx2 to bring about intestinal transformations in oesophageal epithelium. Our results show that Cdx2 can activate a programme of intestinal gene expression when overexpressed in HET-1A cells, or in fetal epithelium, but not in the adult epithelium. This suggests that Cdx2, although necessary for formation of intestinal tissue, is not sufficient to provoke Barrett's metaplasia in adult life and that overexpression of additional transcription factors is necessary. In terms of diet and nutrition, there is a known association of Barrett's metaplasia with obesity. This may work through an increased risk of gastro-oesophageal reflux. Acid and bile are known to activate Cdx2 expression in oesophageal cells. It may also increase circulating levels of TNFalpha (tumour necrosis factor alpha), which activates Cdx2. In addition, there may be effects of diet on the composition of the bile.

Pleural, pancreatic and prostatic involvement in IgG4-related disease mimicking pancreatic head malignancy.

We describe the case of a gentleman with pleural thickening. On follow-up imaging, dilatation of the main pancreatic and common biliary ducts was noted and an initial diagnosis of pancreatic malignancy was made. During his preoperative workup for pancreatic head malignancy, a PET-CT was performed, which demonstrated increased uptake in the pancreas, in the pleura and in the prostate gland. This raised the possibility of immunoglobulin G4-related disease (IgG4-RD), which was effectively treated with oral steroids. IgG4-RD is a well-described cause of autoimmune pancreatitis but can affect other regions, including the pleura and prostate. It is essential that radiologists are aware of the imaging findings in IgG4-RD and can direct clinicians towards this important multisystem diagnosis.

Epithelial metaplasia and the development of cancer.

Metaplasia means the conversion, in postnatal life, of one cell type to another. Understanding the steps leading to metaplasia is important for two reasons. Firstly, it tells us something about the normal developmental biology of the tissues that interconvert. Secondly, metaplasia predisposes to certain forms of neoplasia. So understanding the molecular and cellular mechanisms underlying metaplasia will provide insights into clinical diagnosis and potential therapies. One of the best-described examples of metaplasia is Barrett's metaplasia or the appearance of intestinal-like columnar tissue in the oesophagus. Barrett's metaplasia develops as a result of gastro-oesophageal reflux and is considered the precursor lesion for oesophageal adenocarcinoma. While we know quite a bit about the molecular events associated with the development of oesophageal adenocarcinoma, our understanding of the initial events leading to Barrett's metaplasia is lacking. In the present review we will focus on examples of metaplasia that lead to neoplasia and discuss some of the underlying molecular and cellular mechanisms.

Barrett's esophagus: cancer and molecular biology.

The following paper on the molecular biology of Barrett's esophagus (BE) includes commentaries on signaling pathways central to the development of BE including Hh, NF-κB, and IL-6/STAT3; surgical approaches for esophagectomy and classification of lesions by appropriate therapy; the debate over the merits of minimally invasive esophagectomy versus open surgery; outcomes for patients with pharyngolaryngoesophagectomy; the applications of neoadjuvant chemotherapy and chemoradiotherapy; animal models examining the surgical models of BE and esophageal adenocarcinoma; the roles of various morphogens and Cdx2 in BE; and the use of in vitro BE models for chemoprevention studies.

How does inflammation cause Barrett's metaplasia?

Oesophageal adenocarcinoma conveys a poor prognosis and has a rapidly increasing incidence. Similarly, Barrett's metaplasia (a precursor lesion for oesophageal adenocarcinoma) has an increasing incidence. Both oesophageal adenocarcinoma and Barrett's metaplasia are more common in the context of inflammation as a result of acid and bile reflux. The cytokine profile of Barrett's metaplasia is predominantly a T-helper 2 response that contrasts with the T-helper 1 response in normal and inflamed oesophagus and normal intestine. A key transcription factor in the development of Barrett's metaplasia, CDX2, has recently been shown to be induced in response to inflammatory mediators. The mechanism for induction of CDX2 is dependent on nuclear factor kappa B, a crucial transcription factor in the inflammatory response. Understanding the role of oesophageal inflammation will provide important insight into the development of Barrett's metaplasia and oesophageal cancer.

Cdx genes, inflammation and the pathogenesis of Barrett's metaplasia.

Metaplasia is the conversion of one cell or tissue type to another and can predispose patients to neoplasia. Perhaps one of the best-known examples of metaplasia is Barrett's metaplasia (BM), a pathological condition in which the distal oesophageal epithelium switches from stratified squamous to intestinal-type columnar epithelium. BM predisposes to oesophageal adenocarcinoma and is the consequence of long-term acid bile reflux. The incidence of BM and oesophageal adenocarcinoma has risen dramatically in recent years. A key event in the pathogenesis of BM is the induction of oesophageal CDX2 expression. Importantly, recent data reveal the molecular mechanisms that link inflammation in the development of Barrett's metaplasia, CDX2 and the progression to cancer. This review highlights the relationship between inflammation, metaplasia and carcinogenesis.