Leukotriene A4 signaling, inflammation, and cancer.

Abstract

Chen et al. report in this issue of the Journal that leukotriene A4 hydrolase (LTA4H) was overexpressed in 10 rat esophageal adenocarcinomas compared with matched normal tissue samples (1). They also report that LTA4H was expressed in infiltrating inflammatory cells and in the columnar cells in human esophageal adenocarcinomas. Bestatin, an LTA4H inhibitor, reduced the incidence of esophageal adenocarcinomas by approximately 30% in a rat esophageal carcinoma model. On the basis of these findings, the authors conclude that LTA4H overexpression appears to be an early event in esophageal adenocarcinogenesis and is a potential target for the prevention of esophageal cancer. Chen et al. had previously reported that LTA4H was overexpressed in both human and rat esophageal adenocarcinomas (2). The current results are not too surprising in light of previously published data by this group indicating that nordihydroguaiaretic acid, a lipoxygenase inhibitor, also decreased tumor incidence in this same rat model (3). Cyclooxygenase inhibitors, however, were also effective in reducing the incidence of esophageal adenocarcinomas. Thus, the current study by Chen et al. (1) is a follow-up study evaluating more samples and using an LTA4H inhibitor in vivo. Others (4) have previously reported that LTA4H (also known as Grp94) is overexpressed in lung cancer. About a decade ago, this gene was shown to be overexpressed in a rat kidney fibroblast cell line transformed by v-Ki-ras (5), indicating its potential link to cell transformation. It is generally agreed that chronic tissue inflammation leads to an increase in the risk for the development of cancer (6). After tissue damage or injury, a multifactorial network of molecular signals initiates and maintains a host response. This response involves the activation and directed migration of immune cells. Diseases involving inflammation of the gastrointestinal tract, such as chronic viral hepatitis, ulcerative colitis, and Barrett’s esophagus, lead to an increased risk of cancer in the corresponding site (7,8). Many of the specific mediators associated with chronic inflammation that increase cancer risks have yet to be completely elucidated. However, eicosanoids, such as leukotrienes and prostaglandins, that are bioactive lipid products of arachidonic acid metabolism are mediators of inflammation and have been linked to carcinogenesis (9). The two main pathways for arachidonic acid metabolism involve cyclooxygenases or lipoxygenases. The role of the cyclooxygenase pathway has been reviewed elsewhere (10–12). The precise role of the lipoxygenase pathway in cancer is less clear; however, a convincing story is developing (9). Leukotrienes, such as LTA4 and LTB4, are made predominantly by inflammatory cells such as polymorphonuclear leuko-