Purinergic signaling in hepatocellular carcinoma
Clinical Background
Hepatocellular carcinoma (HCC) is the most common liver cancer in Western countries. Aside from cholangiocarcinoma (CCA, 10-15%) and less frequent entities, HCC accounts for 75-90% of primary liver cancers. Due to the often-late diagnosis and insufficient treatment options in advanced stages, HCC is one of the most frequent cancer-related causes of death worldwide. Patients with liver cirrhosis represent the high-risk group for the development of HCC, regardless of the etiology of liver disease and indeed, HCC is the leading cause of mortality among patients with cirrhosis. Chronic viral hepatitis (hepatitis B and C), heavy alcohol consumption, congenital metabolic disorders, obesity, type 2 diabetes, and aflatoxins represent important risk factors for the development of cirrhosis and complicating HCC. Because of the rising prevalence of obesity, metabolic liver diseases are also associated with a relevant risk for the development of HCC.

Purinergic signaling in HCC
Our group works on the relevance of extracellular purine nucleotides/ nucleosides and purinergic signaling pathways and in acute and chronic liver diseases, including liver cancer. All this work, including ongoing projects, was made possible by the constant and generous support of the German Research Foundation (DFG SCHM 2661/1-1, 1-2, 3-1 and 3-2). Recent own studies indicated that together with cirrhotic liver tissue, HCC cells also express adenosinergic P1 receptors as well as several membrane-bound ectoenzymes involved in the extracellular adenosine metabolism. HepG2 cells have been shown to hydrolyse extracellular ATP to adenosine by means of functionally active ectoenzymes, in vitro, which leads to an activation of MAPK and NF-κB signaling pathways. Our studies further revealed that pharmacological antagonism of A2A receptors results in decreased tumor cell growth and colony formation, in vitro.
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Alteration of growth- and metastasis-promoting properties of adenosine (ADO) by selective adenosine receptor (A2A) antagonists CSC and selective adenosine receptor (A2B) antagonists alloxazine. See also DOI: 10.1111/apt.15089

Complex tumor-immune cell interactions
Complex mechanisms of action of adenosinergic signaling might not be limited to direct effects on the tumor cell. Additional indirect effects of adenosine in the chronically inflamed liver and the tumor microenvironment must be presumed, e.g., modulating effector functions of tumor infiltrating lymphocytes. Evidence of efficacy of combining immunotherapy with targeting the CD39-CD73-A2AR axis is increasing. Targeting different molecules that are involved in generating adenosine may indeed boost anti-tumoral immunity and block a potential mechanism of acquired resistance to immunotherapy. In the case of HCC, we still have little robust functional evidence detailing possible interactions between immune checkpoints and purinergic signaling pathways. Our current efforts are to better understand effects of adenosinergic signaling on complex tumor-immune cell interactions in HCC.

Our Team

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Prof. Dr. Moritz Schmelzle

Principal Investigator

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Dr. rer. nat. Katrin Splith

Postdoc

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Sebastian Knitter

Researcher

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Dr. med. Matthäus Felsenstein

Postdoc

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