Targeting MAPK Signaling in Hepatocellular Carcinoma - Implications for Cell Fate, Microenvironment and Immune Recognition

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal tumors worldwide. So far, the only treatment option for unresectable HCC is the multikinase inhibitor sorafenib, an inhibitor of the Raf/MEK/ERK (MAPK) signaling pathway, which is one of the major pathways implicated in HCC. Although HCC cannot be cured by sorafenib treatment, targeting the MAPK pathway may be a promising strategy for HCC therapy. In order to improve HCC treatment, it is of particular importance to understand the action of sorafenib in more detail. Therefore, a comprehensive analysis of its effects was performed in HCC cells and tissue and compared to specific inhibitors of the MAPK pathway. In my thesis, the following aspects could be demonstrated: 1.Both, Sorafenib and MEK-specific inhibitors repressed the MAPK signaling pathway, but had partially opposite effects on other signaling pathways like Akt signaling. As a consequence, HCC cell numbers were reduced after sorafenib and MEK inhibitor treatment, but cell division was mainly inhibited by sorafenib and to a low extent by the MEK inhibitors. In contrast, apoptosis was stronger induced by the MEK inhibitors, but differences were observed between the cell lines. This suggests that in HCC besides the MAPK pathway other signaling pathways play an important role and need to be targeted in addition to the MAPK pathway. 2.HCC cell lines expressed a variety of surface molecules which are associated with tumor progression. In addition, they secreted several chemokines and growth factors which favor tumorigenesis and angiogenesis. Inhibition of the MAPK pathway modulated both surface molecule expression and secretion of several chemokines and growth factors, whereby, tumor progression is inhibited. 3.NK cells are supposed to be important for fighting against HCC, but in HCC tumor tissue, NK cells were almost absent. There, the microenvironment was altered with an increase of several chemokines and angiogenic factors. These alterations might account for the decreased numbers of NK cells. In vitro treatment of resected HCC tissue with sorafenib resulted in a substantial decrease in the concentration of these increased factors. This indicates that alterations of the microenvironment might be also induced by sorafenib in HCC patients and, thereby, affecting recruitment of immune cells, NK cells in particular, into the tumor tissue.