How does inflammation cause Barrett's metaplasia?

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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.

Introduction

Oesophageal adenocarcinoma (OA) is a cancer with a rapidly increasing incidence and a poor prognosis. OA occurs, as the result of chronic gastro-oesophageal reflux disease (GORD), in metaplastic oesophageal epithelium. Metaplasia describes the conversion, during postnatal life, of one cell (or tissue type) to another [1]. Barrett's metaplasia (BM) is the switch from a stratified squamous to columnar epithelium in the distal oesophagus. Metaplasia often occurs in the context of chronic inflammation and confers an increased risk of cancer [2]. BM, as an example of an intestinal metaplasia, is important because of the vast difference in malignant potential that the new epithelium confers compared with the normal small intestine. Recent advances have linked key inflammatory mediators with transcription factors integral to the development of BM and the progression to OA. The scope of this article is to review the molecular inflammatory processes involved in GORD, BM and OA, and link this with the development of metaplasia. A greater understanding of these processes offers the potential for therapeutic intervention in both BM and OA.

Section snippets

Oesophageal adenocarcinoma

The incidence of OA, a glandular cancer arising in the distal oesophagus, has risen at an alarming rate over the past 30 years. The rate of increase is faster that any other cancer [3] and is centred in the Western world, with the highest rates seen in men in the UK [4]. During a 25-year period from 1979 to 2004 the incidence in white Americans has increased fivefold and continues to rise [5].

OA arises in metaplastic columnar epithelium in the distal oesophagus [6]. The columnar epithelium may

Barrett's metaplasia

BM, as defined by the replacement of normal squamous oesophageal epithelium with columnar epithelium, is a precursor for the development of OA. Whilst most countries require the presence of specialised intestinal cells, such as goblet cells, in the oesophagus to diagnose BM, the current UK guidelines stipulate that any columnar epithelium is sufficient [11]. A diagnosis of BM conveys an increased risk of OA between 30 and 125 times that of the general population [1]. Similar to OA, the

Inflammatory cytokines in oesophagitis and Barrett's metaplasia

BM is considered a complication of the inflammation provoked by the long-term acid and bile reflux [15]. BM occurs in 6–12% of patients with symptomatic GORD compared to less than 2% of a symptom free population, suggesting that the results of GORD are important in the pathogenesis of BM [16]. Inflammation is a common mechanism in the pathogenesis of epithelial metaplasia in many tissues and may induce a change in the commitment of one stem cell to another (e.g. oesophageal stem cell to

Cyclooxygenase 2 (COX-2)

There are two isoforms of Cyclooxygenase (COX): COX-1 and COX-2. COX-2 is induced in response to inflammation and has a role in prostanoid synthesis [23]. The level of COX-2 expression correlates with the degree of acid reflux [24]. COX-2 expression is detected in oesophagitis, BM and OA, and is found at increasing levels from BM, through dysplasia, to OA [25]. Recent evidence has linked specific single nucleotide polymorphisms (SNP) within regulatory regions of the COX-2 gene with an increased

Linking inflammation to Barrett's metaplasia

A link between oesophageal inflammation and cancer has been considered for some time but the evidence for such a link has been weak. However, recent evidence suggests the transcription factor nuclear factor kappa B (NFκB) may be a candidate factor linking inflammation and cancer since it plays a central role in the inflammatory cascade and has been linked to cancer development [32]. Indeed, IL-8 and IL-1β are downstream targets of NFκB, which in turn feedback to increase NFκB activation. NFκB

NFκB and carcinogenesis

The association and causation of molecular pathways involved in inflammation and cancer are generally accepted [51]. The importance of inflammation and NFκB in the development of cancer has been demonstrated in a mouse model of colitis-related colorectal cancer [32]. The inhibitor of NFκB kinase β (IKK-β) IKK phosphorylates NFκ B-bound IκBs and targets them for ubiquitin-dependent degradation and allows liberated NF-kB dimers to enter the nucleus. Targeted inactivation of NFκB in enterocytes by

Conclusion

There is a well-documented association of inflammation and GORD with the development of BM and OA. The levels of inflammatory cytokines expressed in the progression from normal oesophagus, via oesophagitis and BM to OA is different at each stage. Recently key mediators of inflammation, such as NFκB, have been mechanistically linked with the induction of the CDX genes. These genes may play important roles in the initiation of BM. Although there is good epidemiological data that anti-inflammatory

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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