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.
The increased basal expression levels of IL-8 with the progression of Barrett's esophagus constrain NFκB activation and its contribution in the manifestation of Barrett's esophagus. An anti-inflammatory compound, such as curcumin, could create an anti-inflammatory microenvironment and thus potentially support an increase chemosensitivity in EAC cells.
Background Curcumin naturally occurring in curry powder from Curcuma longa is an anti-inflammatory and anti-proliferative agent. It represses NFκB activation and induces apoptosis in cancer cells. Because, inflammation favours the onset of an intestinal metaplasia in esophageal squamous epithelial cells and esophageal carcinoma cells, a reduction of such processes may contribute to establish a stable disease and/or sensitization for chemotherapeutic approaches. Methods Curcumin receptivity was investigated in metaplastic (CP-A), dysplastic (CP-B), adenocarcinoma (OE19, OE33), and esophageal fibroblast (FFE3) cell lines, which were treated with 10 or 25 μM Curcumin for 48h or 72h. Response to Curcumin was measured by proliferation assays as well as by induction of apoptosis and Akt activation by western blot analyses. Results The EAC cell lines OE33 and OE19 show a decrease of proliferation with raising curcumin concentration with an IC50 of 9.6 and 14.8 μM, respectively. While the metaplastic and dysplastic cell lines showed a comparable IC50 of 7.7 and 11.6 μM to the EAC cell lines, the FEF3 cell showed a higher IC50 of approx. 20μM. The phosphorylation of Akt was decreased and apoptosis was induced, showing cleaved PARP, when treated with 25μM curcumin after 48h and 72h. Conclusion Metaplastic, dysplastic and EAC cells show a higher receptivity to curcumin than esophageal fibroblasts cells. This constrains the NFκB activation and its contribution in the manifestation of the Barrett's esophagus. The usage of curcumin to generate an anti-inflammatory microenvironment will potentially help to develop a stable disease or to reverse the development of the Barrett's esophagus. Disclosure All authors have declared no conflicts of interest.
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