Increased expression of the 5‐lipoxygenase pathway and its cellular localization in Barrett’s adenocarcinoma

Abstract

Up-regulation of the 5-lipoxygenase (5-LOX) leukotriene pathway is evident in numerous tumour types, and has been linked to the promotion of cancer cell growth. The aim of this study was to evaluate the immunohistochemical expression of 5-LOX pathway proteins in oesophageal adenocarcinoma and its premalignant lesion, Barrett's metaplasia. Tissue samples were collected at endoscopy from 16 patients with Barrett's metaplasia and from seven with oesophageal adenocarcinoma; five proximal squamous oesophagus samples were used as controls. Immunohistochemical analyses were performed on stromal and epithelial areas with optimized concentrations of primary antibodies for 5-LOX, 5-LOX-activating protein (FLAP), and the distal enzymes leukotriene (LT) A(4) hydrolase (LTA(4) H) and LTC(4) synthase (LTC(4) S). the diagnosis was histologically confirmed from adjacent sections by a gastrointestinal pathologist. Striking increases in the stromal immunoexpression of 5-LOX (P = 0.041), FLAP (P = 0.038), LTA(4) H (P = 0.0008) and LTC(4) S (P = 0.036) were seen in adenocarcinoma tissue. Stromal FLAP and LTA(4) H immunostaining correlated with elevated neutrophil counts (P < 0.001). LTC(4) S was also notably overexpressed within epithelial cells in both Barrett's metaplasia (P < 0.001) and adenocarcinoma (P < 0.01) tissue. Key biosynthetic enzymes of the LTB(4) and LTC(4) biosynthetic pathways are incrementally expressed across the spectrum of squamous, Barrett's metaplasia and oesophageal adenocarcinoma tissues, suggesting, for the first time, a role for both LT subfamilies in disease progression.