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Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
Bertrand Allard1, Célia Jacoberger-Foissac1, Isabelle Cousineau1
1Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada; Faculté de Pharmacie, Université de Montréal, Montreal, QC, Canada.
Abstract:
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.
Insights
Adenosine A2A receptor (A2AR) normally restrains liver cancer. Blocking A2AR worsens obesity, inflammation, and hepatocellular carcinoma (HCC), especially in patients with non-alcoholic steatohepatitis (NASH).
Area of Science:
- Immunology
- Hepatology
- Oncology
Background:
- Adenosine A2A receptor (A2AR) antagonists are explored for cancer immunotherapy.
- A2AR's role in liver cancer (hepatocellular carcinoma, HCC) is not fully understood.
Purpose of the Study:
- To investigate the function of A2AR in hepatocellular carcinoma (HCC) development.
- To determine the impact of A2AR inhibition on obesity, inflammation, and liver cancer.
Main Methods:
- Utilizing Adora2a-deleted mice to study spontaneous and induced HCC.
- Employing conditional gene deletion in myeloid and liver cells.
- Analyzing human HCC patient data for ADORA2A expression and clinical correlation.
Main Results:
- Adora2a deletion induced obesity, non-alcoholic steatohepatitis (NASH), and HCC in mice.
- A2AR signaling in myeloid and hepatocytes suppressed HCC by reducing hepatic inflammation and steatosis.
- A2AR blockade exacerbated HCC, particularly in the context of pre-existing NASH.
- Low ADORA2A gene expression correlated with cirrhosis, inflammation, and poor survival in human HCC.
Conclusions:
- A2AR possesses a previously unrecognized tumor-suppressive role in the liver.
- Caution is advised when using A2AR antagonists in NASH patients and those with NASH-associated HCC.
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