Lead


Lay summary
Surgery offers the only potential cure in many patients with primary or metastatic liver cancer. Extending the limits and improving safety of liver resection would allow more patients to benefit from surgery and to decrease morbidity. The prerequisite for successful and safe liver surgery is the optimal regeneration of the remaining hepatic tissue in order to fulfill the metabolic demands of the patient. Liver regeneration is closely coordinated by paracrine mechanisms. Natural killer (NK) cells are the dominant lymphocyte population in the human liver and have been shown to modulate hepatocellular regeneration and injury after partial liver resection in mice. However, mechanisms that regulate important NK cell functions such as cytotoxicity or cytokine secretion during liver regeneration remain unknown. Extracellular nucleotides such as ATP activate specific purinergic (P2) receptors that are present on a variety of immune cells including NK cells. Levels of extracellular ATP are regulated by enzymatic hydrolysis by ectonucleotidases (mainly CD39/ENTPDase1). Preliminary data reveal that after liver resection, cytotoxicity of wild type NK cells is modulated by extracellular ATP. Alterations of pericellular ATP levels in NK cells null for CD39 was associated with increased proliferation and decreased liver injury after partial liver resection. The purinergic receptor P2Y1 and P2Y2 seem to be involved. Interestingly, cytotoxicity was increased in NK cells with genetic deletion of CD39 compared to wild type NK cells, possibly in response to P2Y receptor desensitization. The general aim of the study is to explore the role of purinergic receptors on NK cell derived cytotoxicity in a mouse model of partial liver resection. Specifically we explore the impact of interactions of extracellular ATP, CD39 and and P2Y receptors on NK cell cytotoxicity in a model of partial liver resection. Significance: Aspects of innate immunity that contribute to liver injury and hepatocellular proliferation during liver regeneration will be investigated in this proposal. Future therapeutic options may result as nucleotides and its derivatives have already been synthesized as small and stable compounds. Their administration could potentially improve hepatic regeneration after major liver resection. This could, ultimately, allow to extend boarders of hepatic resection and to improve patient's outcome for advanced primary and metastatic liver tumors