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Hepatocellular carcinoma (HCC), the most common primary malignant liver tumor, represents one of the most prevalent and deadliest cancers worldwide. Following HCC diagnosis, patients have a median survival time of just 6 to 20 months and a five-year survival rate of less than 20 percent. Recent estimations predict that, without the identification of novel therapeutics, over 1 million people will die as a result of liver cancer in 2030 alone, highlighting the extent of the global health burden presented by HCC. HCC predominantly develops on the basis of a long-standing chronic liver disease (CLD), including chronic viral infection with hepatitis B or C virus, chronic alcohol abuse, non-alcoholic fatty liver disease (NAFLD), autoimmune and chronic cholestatic diseases (such as autoimmune hepatitis, and primary biliary cholestasis) as well as hereditary metabolic syndromes (hereditary hemochromatosis, α1-antitrypsin deficiency and Wilson’s disease). In the majority of cases, CLD has already advanced to cirrhosis by the time HCC is diagnosed. Despite the highly effective anti-viral therapies that have been available for the last number of years, HCC prevalence is also increasing in resource-rich countries including Switzerland. This increase is mainly driven by the ever increasing incidence of NAFLD, resulting from the progressively widespread western lifestyle (characterised by a diet rich in sugar and fat, coupled with a sedentary lifestyle). Such different etiologies, lead to heterogeneous growth patterns and/or cytologic features within tumor that can ultimately challenge the tumor classification and thus compromise the treatment decision. The current treatment options for HCC are mainly determined by the tumor stage and the patient’s individual liver function. While the current gold standard of treatment remains removal of the tumor by ablation, resection or liver transplantation, most patients do not meet the criteria required for surgery.
Liver cancer remains a global health challenge and its incidence is growing worldwide. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. The vast majority of HCCs arise from chronic liver disease such as chronic viral hepatitis, alcohol-induced liver injury or other metabolic, dietary, or toxic factors (as fatty liver disease). Such underlying etiology leads to heterogeneous growth patterns and/or cytologic features within tumor that can ultimately challenge the classification and compromise the treatment.
The aim of this work is to develop a categorization of liver tumors based on histology that is relevant for everyday clinical practice.
We are currently expanding our HCC cohort in order to study the tumors comparatively morphologically and molecularly, especially with regard to the significance of intra-tumor heterogeneity.
Friemel J, Rechsteiner M, Frick L, et al. (2015). Intratumor heterogeneity in hepatocellular carcinoma. Clinical Cancer Research 21(8):1951-61
Köhler UA, Böhm F, et al. (2016). NF-kappaB/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma. Journal of Hepatology 64(1):94-102.
Friemel J*, Frick L*, et al. (2019). Characterization of HCC mouse models: Towards an etiology-oriented subtyping approach. Mol Cancer Res 17(7):1493-1502.
Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in most parts of the Western world. NAFLD encompasses a spectrum of liver conditions ranging from steatosis to a more severe and progressive disease termed nonalcoholic steatohepatitis (NASH). NASH is characterized by hepatocyte injury and apoptosis, hepatic infiltration by inflammatory cells and varying degrees of fibrosis, and may culminate in liver cirrhosis and/or the development of hepatocellular carcinoma. A mouse model based on a choline-deficient high fat diet (CD-HFD), implemented in close collaboration with the Heikenwälder laboratory, allows us to study the morphologic, cellular and molecular mechanisms of fatty liver disease in vivo. In this context, apoptosis plays a key role in the development of HCC encouraging us to investigate the molecular mechanisms underlying the transition from NASH to liver cancer.
We are trying to identify key cellular and molecular determinants of fatty liver disease in mouse models and to validate their relevance to human pathology by correlative analyses in human liver tissues.
Of particular interest is the role of apoptosis in the progression of fatty liver to NASH and liver cancer. Furthermore, we would like to better understand the diagnostic and therapeutic implications of our observation that platelet count, platelet activation and platelet aggregation are increased in murine and human non-alcoholic liver disease, particularly NASH models.
Wolf MJ, Adili A, Piotrowitz K, et al. (2014). Metabolic activation of intrahepatic CD8+ and NKT-cells causes nonalcoholic steatohepatitis and hepatocellular carcinoma via cross-talk with hepatocytes. Cancer Cell 26(4):549-64.
Malehmir M*, Pfister D*, Gallage S*, Szydlowska M*, et al. (2019). Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine 25(4):641-655
Hirsova P*, Bohm F*, et al. (2020). Hepatocyte apoptosis is tumor promoting in murine nonalcoholic steatohepatitis. Cell Death & Disease 11(2):80
