Hepatocellular carcinoma is among the most frequent cancer entities worldwide. Our research group focuses on knowledge-based advances in prevention and early therapy and investigates (1) growth factors and growth factor receptors contributing to the disturbed balance between cell proliferation and cell death in hepatocarcinogenesis, (2) the procarcinogenic role of inflammation, (3) genotoxic and non-genotoxic carcinogens in the environment including nutrition, and (4) epithelial-mesenchymal interactions supporting the development of liver cancer.
In the unaltered liver we found that many fibroblast growth factors (FGF) are produced preferentially in the hepatic mesenchyme. Pro-inflammatory stimuli induce the enhanced synthesis and/or secretion of these factors, which induce selective growth of tumor prestages. In hepatocellular carcinoma FGF9 and at least one member of the FGF8 subfamily are up-regulated in the majority of cases studied.
We found that these FGFs act as survival factors for cancer cells under stress conditions, stimulate growth of tumor-derived myofibroblasts, and induce the proliferation and tube formation of hepatic endothelial cells. Many of these FGFs act via FGFR3 and/or FGFR4. We found that upregulation of FGFR3 or FGFR4 enhances the aggressive phenotype of liver cancer cells, whereas knockdown of these receptors exerts the opposite effect.
Thus, the FGF-FGFR-system supports the development and progression of hepatocellular malignancy.
Hepatocellular carcinoma almost always develops in a chronically inflamed liver. It is assumed that unresolved inflammation evokes cell turnover in an effort to restore tissue homeostasis. In this process, deregulated cytokine production and aberrant cytokine signaling may lead to altered cell growth, differentiation, and apoptosis. The result may be formation and selection of premalignant hepatocytes, which increasingly lose normal growth control and may give rise to cancer. One of our aims is to identify growth factors, which are released upon pro-inflammatory stimuli.
Excessive fat consumption is associated with enhanced lipid storage in the liver (hepatic steatosis) and the risk for the development of hepatitis (non-alcoholic steatohepatitis, NASH) and of liver cancer. The mechanisms underlying the progression of a fatty liver to NASH are not competely known. We have shown that the intake of peroxidized fatty acids, as being present in Western style diet, may trigger the outbreak of hepatic inflammation.We found that peroxidized fatty acids stimulate mesenchymal cells to release pro-inflammatory and growth-inducing cytokines (HB-EGF), which may promote the outgrowth of hepatic malignancy.
Many chemical compounds (drugs, hormones, environmental pollutants) are non-genotoxic carcinogens (NGC). NGC are not mutagenic or toxic to the genetic material and nevertheless they produce tumors. NGC are not identified by currently available short-term in-vitro tests but in long-term animal bioassays only. Further aim of our work is the development of test systems to identify NGC in short-term in-vitro assays in order to replace long-term animal studies. For this purpose a consortium has been founded, which is funded by the EU in the frame of the “Innovative Medicine Initiative” (IMI). In this project we characterize the effects of genotoxic and non-genotoxic carcinogens on cultured cells, intact organs, and cancer prestages at the cellular and molecular level.
We found that some of the NGC induce the release of certain mesenchymal cytokines which leads to activation NFkB in hepatocytes. Following nuclear translocation and transcriptional activity of NFkB, signal cascades are activated that interfere with pro-apoptotic signal transduction pathways. As a consequence, enhanced survival of NGC-treated preneoplastic hepatocytes supports indirectly growth of preneoplasia and enhances the probability for development of cancer.
Some of the NGC induce the production of growth factors (e.g. HGF) in the hepatic mesenchyme. These factors act selectively on preneoplastic lesions triggering their outgrowth to cancer.