WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury

Gastric stem cell research and gastric organoids

“…We assume that confusing consequences in homeostatic status may be related to the use of different reporter systems [47,49]. However, in terms of tumorigenesis, we speculate that the origin of cancer may be chief cells because pre-neoplastic markers including CD44v9 and WFDC2 are expressed from the base immediately after injury [19,81]. Supporting this, H. pylori shows a strong tropism for metaplastic cells in the base of the corpus [82].…”

“…Since cells need to acquire multiple mutagenic events to convert to malignant cells, long-lived stem cells have a greater chance to become CSCs. Considerable evidence has suggested that mature chief cells trans-differentiate into pre-neoplastic cells and can be the origin of gastric cancer Organoid 2022;2:e27 • https://doi.org/10.51335/organoid.2022.2.e27 3 j-organoid.org O [19,45,52,53]. Supporting this, stem cell markers such as TNF receptor superfamily 19 (Troy) and Sox2 are strongly expressed in chief cells of the corpus [37,47].…”

“…The human and mouse stomach consists of 2 representative glandular structures that have distinct cellular lineages: the corpus and antrum [15]. The corpus is the main acid-pro-ducing region of the stomach, and gastric acid-secreting parietal cells are ablated during Helicobacter pylori or Helicobacter felis infection [16] or treatment with metaplasia-inducing chemicals (DMP-777, L-635, high-dose tamoxifen [HDT]) [17][18][19]. These injuries activate the ASCs responsible for mucosal recovery.…”

Stem Cells, Helicobacter pylori, and Mutational Landscape: Utility of Preclinical Models to Understand Carcinogenesis and to Direct Management of Gastric Cancer

“…120 Moreover, recent analyses indicated IL-33 as a key cytokine for SPEM formation. 121,122 Importantly, simultaneous activation of the Wnt and COX-2/PGE2 pathways causes development of intestinal-type gastric tumors, whereas Wnt pathway activation alone induces only limited dysplastic lesions, supporting a role of inflammation in expansion of Wntactivated tumor cells. 119,123 In the inflamed niche, TNF-a signaling is important for gastric tumorigenesis, 124 which further induces activation of NADPH oxidase 1 (NOX1)/ reactive oxygen species (ROS) signaling through NF-kB activation.…”

Follow the Metaplasia: Characteristics and Oncogenic Implications of Metaplasia’s Pattern of Spread Throughout the Stomach

“…Indeed, certain genes upregulated in metaplastic corpus epithelium are highly expressed in antral glands at homeostasis, including DMBT1 ( Sousa et al, 2012 ; Garay et al, 2017 ) and GKN3 ( Menheniott et al, 2010 ; Bockerstett et al, 2020 ), but by the same token, various genes appear to be unique to metaplasia in the corpus, neither expressed in corpus nor antral glands at homeostasis. These include genes such as HE4 ( Jeong et al, 2021 ; Nozaki et al, 2008 ; O'Neal et al, 2013 ), CD44v9 ( Fan et al, 1996 ; Bertaux-Skeirik et al, 2015 ; Bertaux-Skeirik et al, 2017 ; Tsugawa et al, 2019 ), and CLU ( Weis et al, 2013 ; Shimizu et al, 2016 ) , among others ( Weis et al, 2014 ). A more appropriate term to describe these glandular changes (and which will be used in this review to refer to these metaplastic changes) is spasmolytic polypeptide-expressing metaplasia (or SPEM), which is characterized by the expression of the antral spasmolytic polypeptide in the bases of corpus glands ( Schmidt et al, 1999 ) and accurately describes the characteristic features of this metaplastic entity.…”