Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells

Using stable isotope labelling with amino acids of the interacting cell types and the resulting “real-time” monitoring of gene expression during transmigration, we identified molecular alterations in both endothelial as well as Hepatocellular carcinoma cells and validated their relevance in HCC patients

Petra Koudelkova; Victor Costina; Gerhard Weber; Steven Dooley; Peter Findeisen; Peter Winter; Rahul Agarwal; Karin Schlangen; Wolfgang Mikulits


Scholarcy highlights

  • Hepatocellular carcinoma is the sixth most common malignancy worldwide and ranks third in mortality among cancer
  • Analysis of endothelial integrity by transendothelial electrical resistance showed increasing TEER values within 4 days of murine liver sinusoidal endothelial cells cultivation, indicating development of endothelial cell polarity and functional tight junctions sealing the intercellular spaces in the endothelial monolayer
  • Endothelial integrity of mLSECs was maintained between day 4 and day 9 of cultivation, similar to the TEER levels observed with established control HUVEC cells
  • To confirm that the polarity of the endothelial cell layer properly reflects the endothelium in situ for vascular invasion, we examined the mLSEC monolayer attached to the Transwell membrane for expression of the apical polarity marker zonula occludens-1 and the basal polarity marker collagen IV by confocal immunofluoresecence microscopy
  • The Z-view of the stained endothelial monolayer showed a homogenous distribution of both ZO-1 and collagen IV, indicating a basal orientation of the endothelial barrier towards the top side of the Transwell membrane and an apical surface towards the bottom, the latter representing the luminal side of mLSECs
  • Our results suggest a key role of transforming growth factor-β during endothelial transmigration and highlight the active contribution of endothelial cells in this process
  • Barcelona Clinic Liver Cancer Epithelial to mesenchymal transition Collectin 12 Epoxide hydrolase Green fluorescent protein Hepatocellular carcinoma Human umbilical vein endothelial cell Myosin light chain Murine liver sinusoidal endothelial cell Peroxiredoxin-3 Red fluorescent protein Reactive oxygen species Stable isotope labelling with amino acids The cancer genome atlas Transendothelial electrical resistance Transforming growth factor Transgelin-2 Vascular endothelial growth factor Zonula occludens 1

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