Novel key regulatory mechanisms of hepatocellular EMT and HCC dissemination including the receptor tyrosine kinase Axl

Cancer cells invade other tissues either by moving collectively or as single cells via mesenchymal or amoeboid cell types. During carcinoma progression, a variety of tumor cells show changes in their plasticity by morphological and phenotypical conversions such as EMT (Figure 1). In principle, EMT is characterized by loss of epithelial characteristics and the concomitant gain of mesenchymal motility. Furthermore, EMT is described to maintain stem cell properties, to prevent apoptosis and senescence, to suppress immune reactions and to acquire chemoresistance. In this context, the project focuses on EMT-transformation that is induced and maintained by the TGF-beta/PDGF axis and molecularly linked to Wnt/beta-catenin signalling as well asto cap-independent translational control. In addition, we particularly concentrate on novel regulatory molecules such as the receptor tyrosine kinase Axl which might by essentially involved in the EMT of neoplastic hepatocytes. Recent screening approaches of hepatic EMT and fibroproliferative disease models further revealed novel regulatory molecules that might govern various aspects of HCC progression and metastasis (see also: http://resolve.punkt-international.eu/). The overall aim is the identification and characterization of suitable targets for therapeutic intervention with HCC.

Figure 1. Plasticity of invading cancer cells. (A) Collective cell invasion showing tip cells that promote ECM rearrangement. (B) Single cancer cells detach from epithelial clusters by undergoing EMT and exhibiting a rear-front cell polarity. (C) Amoeboid cell movement by loss of cell polarity and chemotaxis in a protease-independent fashion. CAT, collective to amoeboid transition; ECM, extracellular matrix; MAT, mesenchymal to amoeboid transition; MMP, matrix metalloproteinase.