Abstract
TGFβ signaling has been implicated in the metaplasia from squamous epithelia to Barrett's esophagus and, ultimately, esophageal adenocarcinoma. The role of the family member Activin A in Barrett's tumorigenesis is less well established. As tumorigenesis is influenced by factors in the tumor microenvironment, such as fibroblasts and the extracellular matrix, we aimed to determine if epithelial cell-derived Activin affects initiation and progression differently than Activin signaling stimulation from a mimicked stromal source. Using Barrett's esophagus cells, CPB, and the esophageal adenocarcinoma cell lines OE33 and FLO-1, we showed that Activin reduces colony formation only in CPB cells. Epithelial cell overexpression of Activin increased cell migration and invasion in Boyden chamber assays in CPB and FLO-1 cells, which exhibited mesenchymal features such as the expression of the CD44 standard form, vimentin, and MT1-MMP. When grown in organotypic reconstructs, OE33 cells expressed E-cadherin and Keratin 8. As mesenchymal characteristics have been associated with the acquisition of stem cell-like features, we analyzed the expression and localization of SOX9, showing nuclear localization of SOX9 in esophageal CPB and FLO-1 cells.In conclusion, we show a role for autocrine Activin signaling in the regulation of colony formation, cell migration and invasion in Barrett's tumorigenesis.
Highlights
Esophageal adenocarcinoma (EAC) is often thought to arise from a clonal stem-like population of cells, which is potentially responsible for its poor prognosis
Transforming growth factor β (TGFβ) and Activin A have both been implicated in the pathology of esophageal adenocarcinoma [2,3,4, 17]
We first queried publicly available dataset to investigate the expression of Activin A, TGFβ, and components of their signaling cascade during the progression from normal esophagus to esophageal adenocarcinoma
Summary
Esophageal adenocarcinoma (EAC) is often thought to arise from a clonal stem-like population of cells, which is potentially responsible for its poor prognosis. Transforming growth factor β (TGFβ) and Notch signaling pathways play important roles in regulating self-renewal of stem cells and cell-fate determination. Both pathways are frequently implicated in Barrett’s tumorigenesis [1]. It has been shown that loss of members of the TGFβ signaling cascade, such as Smad and β2 spectrin, can contribute to the initiation of Barrett’s esophagus and the progression to esophageal adenocarcinoma through concomitant upregulation of Notch targets Hes and Jagged1 [2]. Analysis of a panel of esophageal adenocarcinoma cell lines demonstrated failed cell cycle arrest after TGFβ stimulation, as they did not respond with the expected down-regulation of c-Myc or the induction p21 [3]. Univariant survival analysis has shown that TGFB1 overexpression was associated with poor prognosis [5]
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