Seminari VHIR - Dr. Jürgen Borlak "Fatty liver disease, cancer stem cells and hepatocellular carcinoma"

Dr. Jürgen Borlak, Director: Professor, Centre for Pharmacology and Toxicology-Institute for Pharmaco- and Toxicogenomics - Hannover, Germany

"Fatty liver disease, cancer stem cells and hepatocellular carcinoma"

The liver is a major site for triacylglycerol synthesis and an important energy reserve of the body. Lipids are stored as lipid droplets in adipose tissue whereas the liver stores energy as glycogen and digested triglycerides in the form of fatty acids. Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Recently, we summarized the molecular pathophysiology of lipid droplet formation in hepatocytes and its link to T2DM, cardiovascular disease and the metabolic syndrome [1]. By now NAFLD has reached epidemic proportion affecting nearly 30% of the European [2] and >45% of the US population [3;4]. Progressive NAFLD leads to cirrhosis, end-stage liver disease requiring liver transplantation [5] and hepatocellular carcinoma and a recent study provided robust evidence for NAFLD being strongly associated with hepatocellular carcinoma (HR, 7.62; 95% CI, 5.76-10.09, Kanwal et al. [6]). However, the underlying mechanisms are unknown but involve the complex interplay of adipokines and cytokines in promoting hepatocarcinogenesis [7;8].
In my presentation I will discuss recent findings on the regulation of cancer stem cells (CSC) in steatotic human hepatoma cells. Specifically, CSCs are enriched after treatment of human hepatoma cells with palmitic acid (PA) and oleic acid (OA). The CSCs were obtained as side cell population using fluorescence activated cell sorting and the Hoechst 3334 dye, e.g. a substrate for the Abcg2 transporter. The lipid treatment induced CSC cell division and proliferation as evidenced by the BrdU label retaining and cell cycle assays. Whole genome scans of sorted SP cells evidenced enriched stem cell marker and informed on highly significant regulations of members of the Hedghock, Notch, PI3K-AKT, EGFR, TGFß, WNT and JAK-STAT signaling pathways thus providing a plethora of opportunities for the development of molecular targeted therapies. Furthermore, by employing the PamGene technology altered activities of serine-threonine and tyrosine kinases in CSC were determined. Importantly, their inhibition with novel dual kinase inhibitors provides a molecular rationale for the

Host: CIBBIM-Nanomedicina. Direccionament i Alliberament Farmacològic - simo.schwartz@vhir.org