Endothelial-mesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1β and TGF-β2. Am J Physiol Cell Physiol 2014 Nov 01;307(9):C859-77
Date
08/29/2014Pubmed ID
25163519Pubmed Central ID
PMC4216936DOI
10.1152/ajpcell.00081.2014Scopus ID
2-s2.0-84908544314 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1β and transforming growth factor-β2 (TGF-β2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1β and TGF-β2 gene silencing in OE33 cells. Recombinant IL-1β and TGF-β2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression.
Author List
Nie L, Lyros O, Medda R, Jovanovic N, Schmidt JL, Otterson MF, Johnson CP, Behmaram B, Shaker R, Rafiee PAuthors
Mary F. Otterson MD Professor in the Surgery department at Medical College of WisconsinReza Shaker MD Assoc Provost, Sr Assoc Dean, Ctr Dir, Chief, Prof in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdenocarcinomaCell Line, Tumor
Cell Movement
Cell Proliferation
Cells, Cultured
Coculture Techniques
Endothelial Cells
Esophageal Neoplasms
Esophagus
Humans
Inflammation Mediators
Interleukin-1beta
Mesoderm
Transforming Growth Factor beta2
Tumor Microenvironment
Vascular Endothelial Growth Factor A
