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In vivo and In vitro Evidence for Transforming Growth Factor-ß1-Mediated Epithelial to Mesenchymal Transition in Esophageal Adenocarcinoma

¹ Medical Research Council Cancer Cell Unit, Hutchison-Medical Research Council Research Centre; ² Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom and ³ Academic Department of Surgery, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom

Requests for reprints: Rebecca C. Fitzgerald, Medical Research Council Cancer Cell Unit, Hutchison-Medical Research Council Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom. Phone: 44-1223-763287; Fax: 44-1223-763296; E-mail: rcf{at}hutchison-mrc.cam.ac.uk.

There is increasing evidence that epithelial to mesenchymal transition (EMT) is involved in cancer progression. Because local invasion and metastasis occurs early in the pathogenesis of esophageal adenocarcinoma, we hypothesized that EMT may be important in this disease. Using immunohistochemistry in a well-characterized set of adenocarcinoma tissues, we showed down-regulation of epithelial markers (E-cadherin and cytokeratin 18) and up-regulation of mesenchymal markers (vimentin and -smooth muscle actin) with concomitant transforming growth factor-ß1 (TGF-ß1) expression at the invasive margin compared with the central tumor. A panel of esophageal cell lines was examined for the ability of TGF-ß1 to induce EMT in vitro. TE7 cells were selected as a model because TGF-ß1 (0-5 ng/mL) treatment induced morphologic and molecular expression changes suggestive of EMT. In TE7 cells, these TGF-ß1-induced changes were reversed by 100 ng/mL of bone morphogenetic protein 7 (BMP7), another member of the TGF-ß1 superfamily. EMT was mediated via canonical TGF-ß1 signaling with concomitant up-regulation of SMAD-interacting protein 1. Alterations in functional variables (aggregation, wounding, motility, and invasion) following TGF-ß1 treatment were consistent with a more invasive phenotype. These functional changes were reversed by BMP7 and SMAD4 RNA interference in vitro. These data suggest that TGF-ß1-mediated EMT may be relevant in esophageal carcinogenesis. (Cancer Res 2006; 66(19): 9583-90)

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				A. Kaimori, J. Potter, J.-y. Kaimori, C. Wang, E. Mezey, and A. Koteish Transforming Growth Factor-beta1 Induces an Epithelial-to-Mesenchymal Transition State in Mouse Hepatocytes in Vitro J. Biol. Chem., July 27, 2007; 282(30): 22089 - 22101. [Abstract] [Full Text] [PDF]

				Correction: EMT in Esophageal Adenocarcinoma Cancer Res., January 1, 2007; 67(1): 427 - 427. [Full Text] [PDF]