Barrett's Metaplasia Meeting
17th-18th September 2009, University of Bath, UK
Cancer of the oesophagus is still uncommon, but its prevalence, and particularly that of the adenocarcimona subtype, is increasing rapidly in many Western countries. This may even be the fastest-growing of all tumour types. The main risk factor for developing this condition is gastro-oesophageal reflux disease (GORD), which is characterised by chronic reflux and heartburn. The damage to the oesophageal epithelium caused by contact with gastric acids and bile is the first step in a cellular progression that can, in some cases, lead to cancer. About 10% of patients with GORD develop an intermediate condition known as Barrett’s Oesophagus (or Barrett’s metaplasia). Those diagnosed with this condition are at a greatly increased risk of developing oesophageal cancer compared even to other patients with GORD; the degree of risk has been equated to the risk of a heavy smoker developing lung cancer.
Barrett’s Oesophagus has no symptoms other than those of the underlying reflux disease. It is characterised by a cellular change (metaplasia) in which the squamous epithelial cells that line the oesophagus are first replaced by the columnar epithelial cells that are characteristic of the normal intestine; this is easily detectable by endoscopy. In later stages the epithelium folds to form intestinal crypts containing mucus-secreting goblet cells.
Understanding the genetic and cellular changes behind the replacement of one type of epithelium with another, and behind the development of adenomas and then carcinomas from Barrett’s cells, is a key to the prevention and treatment of this cancer. These issues were recently discussed in a specialist meeting at the University of Bath, organised by the Biochemical Society. This brought together clinicians and scientists from a wide variety of disciplines, including genetics, epidemiology and, perhaps more surprisingly, developmental biology.
Many questions are still to be answered about the process through which multi-layered squamous epithelial cells are replaced by columnar epithelium. It is not even clear whether the columnar cells migrate from elsewhere in the GI tract, trans-differentiate from squamous cells, or arise from stem cells. Several speakers described searches for genes involved in this transformation. Some, including John Lynch from the University of Pennsylvania, USA, who described models of Barrett’s metaplasia in 3D cell culture, mentioned the transcription factor Cdx2 which has been implicated in this transformation. In the embryo, this gene is expressed in the future intestine but not the future oesophagus, and its expression in cell culture is necessary but not sufficient to induce a change to an intestinal phenotype. Pierre Lao-Sirieix, who works with Rebecca Fitzgerald, one of the meeting organisers, in Cambridge, UK, described genes implicated in the later stages of the process, the progression from Barrett’s through dysplasia to invasive cancer. Interleukin-6 and other “inflammatory” genes were among those identified, which led Lao-Sirieix to speculate that interleukin-6 inhibitors and other anti-inflammatory drugs – perhaps even aspirin – might be useful chemopreventive agents for oesophageal cancer.
In her own lecture, Fitzgerald described changes in gene expression in the stroma underlying epithelial cells during the progression from normal epithelium through Barrett’s metaplasia to cancer. Although some commonly over-expressed genes can be catalogued, the condition is heterogeneous and the expression pattern can differ even between neighbouring crypts in the oesophagus of the same patient. Exposure to acid such as that in gastric reflux and to nitric oxide can induce both gene expression changes and DNA strand breaks.
One of the highlights of the meeting was the Rank Prize Lecture, given by developmental biologist Jonathan Slack who directs the Stem Cell Institute at the University of Minnesota. This prize lecture, funded by film-maker J. Arthur Rank, is given annually by a distinguished exponent of one of Rank’s interests, opto-electronics and nutrition (or animal husbandry). In introducing Slack, Sir Nick Wright, from the Cancer Research UK London Research Institute, praised his broad scientific interests: necessary to bring together nutrition, development and carcinogenesis. Slack described the process of gut development in the embryos of higher vertebrates, in which a single cell sheet differentiates into the different cell types found throughout the tract. The tissue type that develops at each site is determined by transcription factor expression patterns, and changes in these can result in “trans-differentiation” in which one differentiated cell type transforms into another: a process that has been implicated in Barrett’s Oesophagus. And the link with nutrition? “Over-nutrition causes obesity, which makes GORD and thence Barrett’s Oesophagus and cancer more likely”, says Slack.
Gareth Jenkins from the University of Swansea, Wales, discussed the role of exposure to secondary bile acids in carcinogenesis. In reflux, the oesophagus is exposed to a mixture of bile acids of different strength and composition, some of which can diffuse into oesophageal cells. These are thought to induce mitochondrial membrane damage and DNA damage, at least partly through inducing reactive oxygen species. Anti-oxidants and, interestingly, one particular tertiary bile acid, UCDA, are known to be able to block DNA damage and, again, may be useful as chemopreventives.
The final speaker was Wright, who discussed the origins of Barrett’s Oesophagus, again addressing the question of the origin of the metaplastic cells. It has been thought that metaplasia is a clonal process, mediated by stem cells. Were it to be entirely clonal, however, each metaplastic cell would have the same characteristics. Instead, Wright showed using mutation analysis in the cytochrome c-oxidase gene that different clones can arise in separate crypts. When multiple clones do arise in the same individual, only one will progress to malignancy.
Oesophageal cancer is an intractable condition, but like many cancers it is most treatable when it is detected early. It is obviously possible to monitor everyone with Barrett’s carefully with an endoscope, but endoscopy is uncomfortable for the patient and costly for the healthcare provider. As only a small proportion of Barrett’s patients develop cancer, universal screening is unlikely. Any increased understanding of how the condition arises must help select cases for more intensive monitoring, as well as informing drug development. This fascinating meeting, of which only a few highlights are presented here, should have played a part in this.
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