TY - JOUR
T1 - NF-kappa B mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells
AU - Vonach, Caroline
AU - Viola, Katharina
AU - Giessrigl, Benedikt
AU - Huttary, Nicole
AU - Raab, Ingrid
AU - Kalt, Romana
AU - Krieger, Sigurd
AU - Vo, Thanh Phuong Nha
AU - Madlener, Sibylle
AU - Bauer, Sabine
AU - Marian, Brigitte
AU - Hämmerle, Monika
AU - Kretschy, N.
AU - Teichmann, M.
AU - Hantusch, Brigitte
AU - Stary, Susanne J.
AU - Unger, C.
AU - Seelinger, Mareike
AU - Eger, Andreas
AU - Mader, Robert M.
AU - Jäger, Walter
AU - Schmidt, Wolfgang M.
AU - Grusch, Michael
AU - Dolznig, Helmut
AU - Mikulits, Wolfgang
AU - Krupitza, Georg
N1 - ***<REP_Import><OA_Full_2013>132897.28</OA_Full_2013></REP_Import>***
PY - 2011
Y1 - 2011
N2 - 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-kappa B-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 similar to 50% attenuation of CCID formation by treatment of cells with 10 mu M Bay11-7082. Notably, 12(S)-HETE-induced VE-cadherin repression was regulated by either NF-kappa B 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-kB-dependent process of LECs triggering the disintegration of cell-cell contacts, migration, and the generation of CCID.
AB - 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-kappa B-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 similar to 50% attenuation of CCID formation by treatment of cells with 10 mu M Bay11-7082. Notably, 12(S)-HETE-induced VE-cadherin repression was regulated by either NF-kappa B 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-kB-dependent process of LECs triggering the disintegration of cell-cell contacts, migration, and the generation of CCID.
M3 - Article
SN - 0007-0920
VL - 105
SP - 263
EP - 271
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 2
ER -
