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Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma

Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2...

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Autores principales: Allard, Bertrand, Jacoberger-Foissac, Célia, Cousineau, Isabelle, Bareche, Yacine, Buisseret, Laurence, Chrobak, Pavel, Allard, David, Pommey, Sandra, Ah-Pine, Franck, Duquenne, Sebastien, Picard, Fabien, Stagg, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518627/
https://www.ncbi.nlm.nih.gov/pubmed/37729873
http://dx.doi.org/10.1016/j.xcrm.2023.101188
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author Allard, Bertrand
Jacoberger-Foissac, Célia
Cousineau, Isabelle
Bareche, Yacine
Buisseret, Laurence
Chrobak, Pavel
Allard, David
Pommey, Sandra
Ah-Pine, Franck
Duquenne, Sebastien
Picard, Fabien
Stagg, John
author_facet Allard, Bertrand
Jacoberger-Foissac, Célia
Cousineau, Isabelle
Bareche, Yacine
Buisseret, Laurence
Chrobak, Pavel
Allard, David
Pommey, Sandra
Ah-Pine, Franck
Duquenne, Sebastien
Picard, Fabien
Stagg, John
author_sort Allard, Bertrand
collection PubMed
description Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC.
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spelling pubmed-105186272023-09-26 Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma Allard, Bertrand Jacoberger-Foissac, Célia Cousineau, Isabelle Bareche, Yacine Buisseret, Laurence Chrobak, Pavel Allard, David Pommey, Sandra Ah-Pine, Franck Duquenne, Sebastien Picard, Fabien Stagg, John Cell Rep Med Article Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC. Elsevier 2023-09-19 /pmc/articles/PMC10518627/ /pubmed/37729873 http://dx.doi.org/10.1016/j.xcrm.2023.101188 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Allard, Bertrand
Jacoberger-Foissac, Célia
Cousineau, Isabelle
Bareche, Yacine
Buisseret, Laurence
Chrobak, Pavel
Allard, David
Pommey, Sandra
Ah-Pine, Franck
Duquenne, Sebastien
Picard, Fabien
Stagg, John
Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title_full Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title_fullStr Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title_full_unstemmed Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title_short Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
title_sort adenosine a2a receptor is a tumor suppressor of nash-associated hepatocellular carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518627/
https://www.ncbi.nlm.nih.gov/pubmed/37729873
http://dx.doi.org/10.1016/j.xcrm.2023.101188
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