Role of TGF-beta in transendothelial migration and intrahepatic metastasis of liver cancer

Hepatocellular EMT correlates with important aspects of HCC invasion and intrahepatic metastasis. In this project we will exploit 3-dimensional (3D) hepatic cell cultures (hepatospheres) of EMT to assess the transforming growth factor (TGF)-beta dependent mechanisms underlying local cell invasion and the transendothelial migration of HCC cells into the vasculature, the latter process termed hepatic intravasation. Labeled heterotypic 3D cultures allow particularly studying phenotypic changes of epithelial HCC cells upon paracrine TGF-beta regulation provided by the tumor-stroma. Intravasation of malignant hepatocytes into blood vessels is mimicked by cocultivation of HCC cells with hepatic sinusoidal endothelial cells in heterotypic hepatospheres. Importantly, we tackle the question whether TGF-beta driven EMT is essentially required for hepatic intravasation. The efficacy of anti-TGF-beta drugs will be further investigated in 3D models by their ability to block invasion and intravasation of HCC cells, which both aredruggable key events in intrahepatic metastasis (see also website of EU-FP7-PEOPLE-2012-ITN “IT-LIVER”)