Blockade of A(2A) receptors potently suppresses the metastasis of CD73( ) tumors
Paul A Beavis, Upulie Divisekera, Christophe Paget, Melvyn T Chow, Liza B John, Christel Devaud, Karen Dwyer, John Stagg, Mark J Smyth, Phillip K Darcy
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2013
CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic funct..View full abstract
The authors acknowledge the assistance of the Peter MacCallum Cancer Centre Experimental Animal facility technicians for animal care, the Histology Department (Peter MacCallum Cancer Centre) for the processing of hematoxylin and eosin sections of lung tissue, and Dr. Delphine Denoyer for her assistance with TLC analysis. The authors also acknowledge Bayer for provision of the A<INF>2B</INF> agonist BAY60-6583. This work was funded by project grants from the National Health and Medical Research Council (NHMRC) and Susan G. Komen for the Cure, an American Department of Defense Breast Cancer Fellowship (to C.P.), an NHMRC Australian Research Fellowship (to M.J.S. and P.A.B.), an NHMRC Senior Research Fellowship (to P.K.D.), and a Famille Sabourin Research Chair of University of Montreal and Operating Grant from the Canadian Institutes of Health Research (to J.S.).