Unraveling a New Role for Claudins in Gastric Tumorigenesis

Abstract

astric cancer pathogenesis is a multistep process Gthat is associated with Helicobacter pylori infection as an important risk factor. The progression of mucosal pathology through the Correa cascade begins with acute gastritis, which is followed by chronic active gastritis, atrophic gastritis, intestinal metaplasia/dysplasia, and then gastric cancer. A high prevalence of gastric cancer remains; there were more than 1 million new cases in 2018 worldwide, and the mortality rates of gastric cancer among all cancers are third for men and fourth for women. Despite H pylori eradication therapy and improved surveillance, pockets of high incidence and mortality still occur in Asia, South and Central America, and Eastern Europe. Furthermore, mortality rates worldwide have not improved much in the past 20 years despite our growing knowledge of the factors regulating gastric cancer pathogenesis, including the biology of H pylori, environmental factors including diet and toxins, and epithelial factors including oxidative damage. One emerging area providing new insights into gastric cancer pathogenesis is tight junction dysfunction, which contributes to neoplasia development during H pylori infection. Advances in animal models and in molecular techniques have facilitated the discovery of important new ideas about tight junction dysfunction in the stomach and its link to gastric tumorigenesis. Tight junction dysfunction occurs in the gastrointestinal tract when the barrier is no longer selective and tissue homeostasis is disrupted as a result of dysfunction of transporters that depend on ion gradients. The main contributors to selective permeability at tight junctions are claudins, a family of membrane-bound, tetraspanning, and pore-forming proteins. There are currently 27 known members of the human claudin gene family, each thought to confer unique selectivity to the passage of charged and uncharged solutes. Claudin expression defines paracellular permeability, and expression of specific family members varies between tissues. The major claudin expressed in stomach is claudin-18 (CLDN18A2.1; the CLDN18A1.1 is expressed primarily in lung). Patients with gastric cancer showed claudin-18 loss (both lung and stomach isoforms) early in the Correa cascade, and claudin-18 loss was an independent predictor of poor prognosis in patients with gastric cancer. Knockout of Cldn18A2.1 in mice (stCldn18knockout [KO]) increased apical to basolateral Hþ-flux and caused atrophic gastritis despite compensatory Cldn18A1.1 expression at tight junctions. In contrast, studies using mice deficient in both Cldn18A2.1 and Cldn18A1.1 recently showed that claudin-18 loss drives neoplasia and tumor formation in the absence of H pylori infection, which provides mechanistic insight into effectors that participate in proliferation, stem cell homeostasis, neoplasia development, and tumorigenesis.