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: Claudia Sorrentino, Lucio Miele, Amalia Porta, Aldo Pinto, Silvana Morello
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 29 Pg. 27478-89 (Sep 29 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26317647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Angiogenesis Inducing Agents
• Angiogenesis Inhibitors
• Antigens, Ly
• BAY 60-6583
• CD11b Antigen
• Ly6G antigen, mouse
• Receptor, Adenosine A2B
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Aminopyridines (chemistry)
• Angiogenesis Inducing Agents (metabolism)
• Angiogenesis Inhibitors (metabolism)
• Animals
• Antigens, Ly (metabolism)
• CD11b Antigen (metabolism)
• Disease Models, Animal
• Female
• Flow Cytometry
• Melanoma (metabolism)
• Melanoma, Experimental
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (cytology)
• Neovascularization, Pathologic
• Receptor, Adenosine A2B (metabolism)
• Skin Neoplasms (metabolism)
• T-Lymphocytes (pathology)
• Tumor Microenvironment
• Vascular Endothelial Growth Factor A (metabolism)