Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/Entpd1 null Mice12. Issue 1 (7th January 2013)

• Record Type: Journal Article
• Authors: Sun, Xiaofeng; Han, Lihui; Seth, Pankaj; Bian, Shu; Li, Linglin; Csizmadia, Eva; Junger, Wolfgang G.; Schmelzle, Moritz; Usheva, Anny; Tapper, Elliot B.; Baffy, Gyorgy; Sukhatme, Vikas P.; Wu, Yan; Robson, Simon C.
• Is Part Of: Hepatology. Volume 57:Issue 1(2013:Jan.)
• Page Start: 205
• Page End: 216
• Publication Date: 2013-01-07
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.25989
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Liver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism, and aberrant cell proliferation. Nucleoside triphosphate diphosphohydrolase‐1; (CD39/ENTPD1) is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. These properties inhibit antitumor immune responses and promote angiogenesis, being permissive for the growth of transplanted tumors. Here we show that <italic>Cd39</italic> deletion promotes development of both induced and spontaneous autochthonous liver cancer in mice. Loss of <italic>Cd39</italic> results in higher concentrations of extracellular nucleotides, which stimulate proliferation of hepatocytes, abrogate autophagy, and disrupt glycolytic metabolism. Constitutive activation of Ras‐mitogen‐activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR)‐S6K1 pathways occurs in both quiescent <italic>Cd39</italic> null hepatocytes <italic>in vitro</italic> and liver tissues <italic>in vivo</italic>. Exogenous adenosine 5′‐triphosphate (ATP) boosts these signaling pathways, whereas rapamycin inhibits such aberrant responses in hepatocytes. <italic>Conclusion</italic>: Deletion of <italic>Cd39</italic> and resulting changes in disordered purinergic signaling perturb hepatocellular metabolic/proliferative responses, paradoxically resulting in malignant transformation. These findings might impact adjunctive therapies for cancer. Our studies indicate that the biology of autochthonous and transplanted tumors is quite distinct. (H<sc>EPATOLOGY</sc> 2013)</p> </abstract>