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.
Aim
he esophageal adenocarcinoma (EAC) is characterized by an early lymphogenic dissemination and a poor prognosis. The tumor biology and the impact of autocrine, paracrine and endocrine mediators are involved in these mechanisms. For dissemination, the tumor cells need to escape the solid tumor and invade into new target structures. This mechanism is described as epitheliale-mesenchymal transition (EMT), which could be initiated by TGF-beta
Methods
Two proliferation and motility of the esophageal adenocarcinoma cell lines (OE33, OE19) were analyzed after TGF-beta1 and TGF-beta2 treatment. EMT marker gene expressions (e.g. vimentin) were assessed by qRT-PCR.
Results
TGF-beta2 led to a deceased proliferation rate compared to untreated and TGF-beta1 treated cells in OE33 cells. In OE19 cells both, TGF-beta1 and TGF-beta2 treatment resulted in an increased proliferation compared to untreated cells. In OE33 cells the motility was affected by TGF-beta1 only, while in OE19 cells the motility was increased by TGF-beta1 and TGF-beta2 compared to untreated cells. The vimentin mRNA-expression in OE33 cells was increased by TGF-beta1 and TGF-beta2 (14.7-fold and 25.9-fold). However TGF-beta1 and TGF-beta2 only led to a moderate increase in the vimentin mRNA-expression (4.0-fold and 1.8-fold) in OE19 cells.
Conclusion
TGF-beta1 and TGF-beta2 induce EMT and cellular motility in a cell line specific pattern. The responsible intracellular signaling cascades addressed by TGF-beta1 and TGF-beta2 and their contribution for dissemination in EAC patients need to be investigated with full details.
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