NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells

C. Vonach, K. Viola, B. Giessrigl, N. Huttary, I. Raab, R. Kalt, S. Krieger, T.P.N. Vo, S. Madlener, S. Bauer, B. Marian, M. Hämmerle, N. Kretschy, M. Teichmann, B. Hantusch, S. Stary, C. Unger, M. Seelinger, A. Eger, R. MaderW. Jäger, W. Schmidt, M. Grusch, H. Dolznig, W. Mikulits, G. Krupitza

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung


Background:The intravasation of breast cancer into the lymphendothelium is an early step of metastasis. Little is known about the mechanisms of bulky cancer invasion into lymph ducts.Methods:To particularly address this issue, we developed a 3-dimensional co-culture model involving MCF-7 breast cancer cell spheroids and telomerase-immortalised human lymphendothelial cell (LEC) monolayers, which resembles intravasation in vivo and correlated the malignant phenotype with specific protein expression of LECs.Results:We show that tumour spheroids generate circular chemorepellent-induced defects (CCID) in LEC monolayers through retraction of LECs, which was induced by 12(S)- hydroxyeicosatetraenoic acid (HETE) secreted by MCF-7 spheroids. This 12(S)-HETE-regulated retraction of LECs during intravasation particularly allowed us to investigate the key regulators involved in the motility and plasticity of LECs. In all, 12(S)-HETE induced pro-metastatic protein expression patterns and showed NF-κB-dependent up-regulation of the mesenchymal marker protein S100A4 and of transcriptional repressor ZEB1 concomittant with down-regulation of the endothelial adherence junction component VE-cadherin. This was in accordance with 50% attenuation of CCID formation by treatment of cells with 10 M Bay11-7082. Notably, 12(S)-HETE-induced VE-cadherin repression was regulated by either NF-κB or by ZEB1 since ZEB1 siRNA knockdown abrogated not only 12(S)-HETE-mediated VE-cadherin repression but inhibited VE-cadherin expression in general.Interpretation:These data suggest an endothelial to mesenchymal transition-like process of LECs, which induces single cell motility during endothelial transmigration of breast carcinoma cells. In conclusion, this study demonstrates that the 12(S)-HETE-induced intravasation of MCF-7 spheroids through LECs require an NF-κB-dependent process of LECs triggering the disintegration of cell-cell contacts, migration, and the generation of CCID. © 2011 Cancer Research UK All rights reserved.
Seiten (von - bis)263-271
FachzeitschriftBritish Journal of Cancer
PublikationsstatusVeröffentlicht - 12 Juli 2011


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