title: Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model.
abstract: Vascular endothelial growth factor (VEGF) is an angiogenic factor critically involved in tumor progression. Adenosine A2B receptor plays a pivotal role in promoting tumor growth. The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSCs) in the pro-angiogenic effects of A2B and to determine whether A2B blockade could enhance the effectiveness of anti-VEGF treatment. Mice treated with Bay60-6583, a selective A2B receptor agonist, showed enhanced tumor VEGF-A expression and vessel density. This effect was associated with accelerated tumor growth, which could be reversed with anti-VEGF treatment. Bay60-6583 increased the accumulation of tumor CD11b+Gr1+ cells. Depletion of MDSCs in mice significantly reduced A2B-induced VEGF production. However, A2B receptor stimulation did not directly regulate VEGF expression in isolated tumor myeloid cells. Mechanistically, Bay60-6583-treated melanoma tissues showed increased STAT3 activation. Inhibition of STAT3 significantly decreased the pro-tumor activity of Bay60-6583 and reduced tumor VEGF expression. Pharmacological blockade of A2B receptor with PSB1115 significantly reduced tumor growth by inhibiting tumor angiogenesis and increasing T cells numbers within the tumor microenvironment. These effects are, at least in part, dependent on impaired tumor accumulation of Gr1+ cells upon A2B receptor blockade. PSB1115 increased the effectiveness of anti-VEGF treatment.
authors: Department of Pharmacy, University of Salerno, Fisciano SA, Italy.
authors: Claudia
authors: C
authors: Sorrentino
authors: Department of Genetics, School of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors: Lucio
authors: L
authors: Miele
authors: Department of Pharmacy, University of Salerno, Fisciano SA, Italy.
authors: Amalia
authors: A
authors: Porta
authors: Department of Pharmacy, University of Salerno, Fisciano SA, Italy.
authors: Aldo
authors: A
authors: Pinto
authors: Department of Pharmacy, University of Salerno, Fisciano SA, Italy.
authors: Silvana
authors: S
authors: Morello
mesh_terms: D000631:Aminopyridines / Q000737:chemistry; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D009389:Neovascularization, Pathologic; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000950:Antigens, Ly; C518875:BAY 60-6583; D039481:CD11b Antigen; C480309:Ly6G antigen, mouse; D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: A2B adenosine receptor; melanoma; myeloid-derived suppressor cells; tumor angiogenesis