The Role of Wnt and R-spondin in the Stomach During Health and Disease

Abstract

The Wnt signaling pathway is one of the most prominent developmental signals. In addition to its functions in development, there is emerging evidence that it is also crucial for various organ functions in adult organisms, where Wnt signaling controls tissue stem cell behavior, proliferation and differentiation. Deregulation of Wnt signaling is involved in various pathological conditions and has been linked to malignant tissue transformation in different organ systems. The study of the Wnt signaling pathway has revealed a complex regulatory network that tightly balances the quality and strength of Wnt signaling in tissues. In this context, R-spondins are secreted proteins that stabilize Wnt receptors and enhance Wnt signaling. In this review we focus on new insights into the regulatory function of Wnt and R-spondin signaling in the stomach. In addition to its function in the healthy state, we highlight the connection between Wnt signaling and infection with Helicobacter pylori (H. pylori), a pathogen that colonizes the stomach and is the main risk factor for gastric cancer. In addition to experimental data that link Wnt signaling to carcinogenesis, we discuss that Wnt signaling is affected in a substantial proportion of patients with gastric cancer, and provide examples for potential clinical implications for altered Wnt signaling in gastric cancer.

Keywords: Axin2; Helicobacter pylori; Lgr5+ stem cells; R-spondin; Wnt signaling; gastric cancer; stem cells.

Figure 1

The Wnt and R-spondin signaling pathway: In the absence of R-spondin (-Rspo), the membrane ubiquitinase zinc and ring finger 3/ ring finger 43 (ZNRF3/RNF43) associates with the Wnt receptor complex Frizzled/ Low-density lipoprotein receptor-related protein 5/6 (Fzd/LRP5/6), inducing its internalization and preventing its Wnt dependent phosphorylation, thereby inhibiting the downstream Wnt signaling cascade. In the presence of R-spondin (+Rspo), the ubiquitinase ZNRF3/RNF43 is internalized, enabling Wnt dependent phosphorylation of LRP5/6 and Dishevelled (DVL) as well as inhibition of glycogen synthase kinase-3 beta (GSK3beta). This then leads to the stabilization of the transcription factor beta-catenin (β-cat), its translocation in the nucleus and the subsequent expression of Wnt target genes.

Figure 2

Composition of the homeostatic antrum gland: The stem cell compartment is located at the base of the gland consisting of a basal Axin2+/Lgr5+ stem cell population and a further apical Axin2+/Lgr5- stem cell population. Myofibroblasts of the lamina muscularis mucosae produce R-spondin3 and Wnt, which fuel the proliferation of both stem cell populations. Their progenies are pushed towards the top of the gland, thereby renewing the antrum gland within 7 days by Axin2+/Lgr5- cells or within 14 days by Axin2+/Lgr5+ cells.