In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett’s sequence

Abstract

Background An altered Wnt-signaling activation has been reported during Barrett’s esophagus progression, but with rarely detected mutations in APC and β-catenin (CTNNB1) genes. Methods In this study, a robust in-depth expression pattern analysis of frizzled receptors, co-receptors, the Wnt-ligands Wnt3a and Wnt5a, the Wnt-signaling downstream targets Axin2, and CyclinD1, as well as the activation of the intracellular signaling kinases Akt and GSK3β was performed in an in vitro cell culture model of Barrett’s esophagus. Representing the Barrett’s sequence, we used normal esophageal squamous epithelium (EPC-1, EPC-2), metaplasia (CP-A) and dysplasia (CP-B) to esophageal adenocarcinoma (EAC) cell lines (OE33, OE19) and primary specimens of squamous epithelium, metaplasia and EAC. Results A loss of Wnt3a expression was observed beginning from the metaplastic cell line CP-A towards dysplasia (CP-B) and EAC (OE33 and OE19), confirmed by a lower staining index of WNT3A in Barrett’s metaplasia and EAC, than in squamous epithelium specimens. Frizzled 1–10 expression analysis revealed a distinct expression pattern, showing the highest expression for Fzd2, Fzd3, Fzd4, Fzd5, Fzd7, and the co-receptor LRP5/6 in EAC cells, while Fzd3 and Fzd7 were rarely expressed in primary specimens from squamous epithelium. Conclusion Despite the absence of an in-depth characterization of Wnt-signaling-associated receptors in Barrett’s esophagus, by showing variations of the Fzd- and co-receptor profiles, we provide evidence to have a significant role during Barrett’s progression and the underlying pathological mechanisms. Electronic supplementary material The online version of this article (10.1186/s12876-019-0957-5) contains supplementary material, which is available to authorized users.

Cancer chemoprevention through Frizzled receptors and EMT

“…Human oral squamous cell carcinoma [38] Upregulated Hepatocellular carcinoma [39] Upregulated Esophageal adenocarcinoma [66] Upregulated Colorectal adenomas [66] Downregulated FZD3…”

“…A comparison between FZD2 knockdown and overexpression found that 889 genes varied in expression, many of which were identified to induce EMT, extracellular-matrix organization, cell adhesion, angiogenesis, and morphogenesis [ 41 ]. FZD2 is highly expressed in premalignant lesions preceding esophageal adenocarcinoma but is decreased in colorectal adenomas compared to normal tissue, suggesting FZD2 could be targeted differently to intercept early lesions depending on the tissue type [ 43 ]. The minimal expression of FZD2 in normal adult tissues, along with substantial evidence of EMT promotion, highlights the chemopreventive potential of targeting FZD2.…”

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms

“…1a ). Interestingly, many of these factors contribute to the maintenance of epithelial homeostasis and regeneration in digestive tissues including colon and esophagus 8 , 28 , 29 . In line with this, an Ingenuity Pathway Analysis linked the LIGHT down-regulated transcriptome to processes such as cellular and tissue growth or development, epithelial to mesenchymal transition and cell-to-cell communication (Supplementary Fig.…”

Xenopus epidermal and endodermal epithelia as models for mucociliary epithelial evolution, disease, and metaplasia

“…Barrett's esophagus and gastric ciliated metaplasia are considered precancerous conditions indicating increased risk to develop cancer, and MCCs were also frequently found in association with gastric adenocarcinoma (Bishop, Perrino, Ruzinova, & Brunt, 2015; Loy, 1994; Rubio, Kato, Kitagawa, Sugano, & Grimelius, 1988; Torikata & Mukai, 1990; Torikata, Mukai, & Kawakita, 1990). Dysregulation of Wnt signaling and alterations in ΔN‐tp63 were connected to Barrett's esophagus formation in the mouse and in humans (Clément, Braunschweig, Pasquier, Bosman, & Benhattar, 2006; Götzel et al, 2019; Lefort & Dotto, 2011; Wang et al, 2011). Additionally, gastric ciliated metaplasia in the mouse can be induced by loss of gastric H + /K + ATPase.…”