title: Anti-CD73 therapy impairs tumor angiogenesis.
abstract: CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, H2L 4M1, Canada.
authors: Bertrand
authors: B
authors: Allard
authors: Martin
authors: M
authors: Turcotte
authors: Kathleen
authors: K
authors: Spring
authors: Sandra
authors: S
authors: Pommey
authors: Isabelle
authors: I
authors: Royal
authors: John
authors: J
authors: Stagg
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000098:blood supply / Q000276:immunology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D015720:5'-Nucleotidase; C548241:NT5E protein, human
keywords: CD73; adenosine; cancer therapy; tumor angiogenesis