In vivo and in vitro evidence for transforming growth factor-beta1-mediated epithelial to mesenchymal transition in esophageal adenocarcinoma.
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 alpha-smooth muscle actin) with concomitant transforming growth factor-beta1 (TGF-beta1) expression at the invasive margin compared with the central tumor. A panel of esophageal cell lines was examined for the ability of TGF-beta1 to induce EMT in vitro. TE7 cells were selected as a model because TGF-beta1 (0-5 ng/mL) treatment induced morphologic and molecular expression changes suggestive of EMT. In TE7 cells, these TGF-beta1-induced changes were reversed by 100 ng/mL of bone morphogenetic protein 7 (BMP7), another member of the TGF-beta1 superfamily. EMT was mediated via canonical TGF-beta1 signaling with concomitant up-regulation of SMAD-interacting protein 1. Alterations in functional variables (aggregation, wounding, motility, and invasion) following TGF-beta1 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-beta1-mediated EMT may be relevant in esophageal carcinogenesis.
Rees
Jonathan R E
JR
Medical Research Council Cancer Cell Unit, Hutchison-Medical Research Council Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom.
Onwuegbusi
Benjamin A
BA
Save
Vicki E
VE
Alderson
Derek
D
Fitzgerald
Rebecca C
RC
D000230:Adenocarcinoma / Q000473:pathology*; D001471:Barrett Esophagus / Q000473:pathology*; D014408:Biomarkers, Tumor; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000032:analysis / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000473:pathology*; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000737:chemistry; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*
C525819:BMP7 protein, human; D014408:Biomarkers, Tumor; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C108381:GEMIN2 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1