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The Function of inflammatory signalling pathways in acute and chronic liver disease and liver cancer

Final Report Summary - LUEDDE-MED3-AACHEN (The Function of inflammatory signalling pathways in acute and chronic liver disease and liver cancer)

Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and the malignant tumour with the highest rise in incidence of all cancers world-wide. In most instances, HCCs do not arise in a healthy liver but in a setting of chronic inflammation and subsequent liver fibrosis. While the linkage between inflammation and cancer in the liver has been known for some time now, the molecular mechanisms driving tumourigenesis are still unknown. Therefore, currently no pharmacological strategy exists to prevent liver cancer in patients with chronic liver inflammation that cannot be cured from their underlying liver disease.

In this grant proposal, we have examined molecular mechanisms of liver cancer development by using genetically modified mouse models. The focus of our work was the cytokine “tumour necrosis factor” (TNF), a soluble “messenger” molecule that is secreted by inflammatory cells and binds to its specific receptor on the cell surface of other cells where it triggers the activation of several inflammatory signaling pathways. Specifically, we have identified several previously unrecognised molecular pathways and molecules downstream of the TNF receptor that play important roles in liver fibrosis and hepatocarcinogenesis. First, we demonstrated that NEMO, a molecule known to activate the inflammatory NF-kappaB pathway, also controls an NF-kappaB-independent pathway to liver cancer that depends on the functionality of the molecule TAK1. Moreover, we demonstrated that this pathway leads to defined “hot-spot” aberrations on chromosomes in liver tumours. In a follow-up project, we could show that TAK1 controls different forms of programmed cell death. We showed that apoptosis and programmed necrosis - a novel form of programmed cell death controlled by the molecule RIP3 - might play opposing roles in controlling the transition from chronic inflammation to liver cancer by differentially regulating immune cell responses and compensatory cell regeneration. In a translational approach to clinical Hepatology, we demonstrated that programmed necrosis might be especially important in the progression from fatty liver disease towards its fatal consequences, liver fibrosis and cancer. Finally, we identified a network of micro RNAs, small, non-coding RNA molecules, in hepatic stellate cells that serve as signaling nexus between inflammation and fibrogenesis in murine and human liver fibrosis.

Together, we identified different molecular pathways and cell death programmes that might serve as targets for novel pharmacological strategies against liver fibrosis and liver cancer. Given that obesity and fatty liver disease are becoming an increasing problem within most EU countries, especially our findings on programmed necrosis in this clinical context might lead to clinical study approaches and a future benefit for patients with chronic liver disease.