Barrett's oesophagus and oesophageal adenocarcinoma: how does acid interfere with cell proliferation and differentiation?

Abstract

Acid, a principal component of gastro-oesophageal refluxate, may contribute to the development and malignant progression of Barrett's oesophagus. Oesophageal pH monitoring studies have demonstrated that patients with Barrett's oesophagus have severe and chronic acid reflux. However, there is overlap between the amount of acid exposure in patients with oesophagitis compared with patients with Barrett's oesophagus. This suggests that factors other than acid may be important in the aberrant oesophageal cell differentiation process that leads to the development of the metaplastic Barrett's mucosa. The other factors important in the aetiology of Barrett's oesophagus are poorly understood but probably include both genetic and environmental factors.

Figure 1

Abnormal differentiation status of the Barrett's epithelium. (A) and (B) low and high power fields, respectively, of alcian blue staining in Barrett's oesophageal sections showing the blue acidic and neutral mucins in goblet and non-goblet columnar cells. (C) PAS–alcian blue staining for neutral mucins (magenta) and N-acetylated sialo-mucins (blue) found in type IIB intestinal metaplasia. (D) the same PAS–alcian blue staining in duodenal section, note that mucins here are mainly neutral (magenta). (E) a high iron diamine–alcian blue staining showing dark brown sulphomucins characteristic of type IIB incomplete IM.

Figure 2

Abnormal proliferation compartments of Barrett's oesophagus and associated dysplasia. Expression of a proliferation marker mini-chromosome maintenance protein (Mcm2) is shown by immunohistochemistry. Whereas the proliferative compartment is confined to the basal layers (normal squamous oesophagus, (A)) and in the crypts and the glands (normal stomach and duodenum, (B) and (C)), in Barrett's metaplasia proliferation extends towards the surface (D). With increasing dysplasia the number of proliferating cells increases with expansion of the proliferative compartment (E-G).

Figure 3

Acid and other luminal constituents may lead to a hyperproliferative and anti-apoptotic response of Barrett's epithelial cells. This in turn may lead to an accumulation of genetic abnormalities through a vicious cycle effect. The somatic mutations may be accumulated in a non-predictable order. Cancer will occur once the mutation(s) provides the cells with the capacity to invade.