Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma
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Chase Taylor1,*, Holli A. Loomans2,*, Gregoire F. Le Bras1, Rainelli B. Koumangoye1, Alejandra I. Romero-Morales1, Laura L. Quast1, Alexander I. Zaika1,2,3,4, Wael El-Rifai1,2,3,4, Thomas Andl5, Claudia D. Andl1,2,3,4
1Departments of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA
2Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA
3Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA
4Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA
5Division of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA
*These authors have contributed equally to this work
Claudia D. Andl, e-mail: [email protected]
Keywords: Barrett's esophagus, esophageal adenocarcinoma, SOX9
Received: March 11, 2015 Accepted: September 24, 2015 Published: October 06, 2015
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.
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