Host A(2B) adenosine receptors promote carcinoma growth.
Recent studies suggest that tumor-infiltrating immune cells can benefit the tumor by producing factors that promote angiogenesis and suppress immunity. Because the tumor microenvironment is characterized by high adenosine levels, we hypothesized that the low-affinity A(2B) adenosine receptor located on host immune cells may participate in these effects. In the current study, we tested this hypothesis in a Lewis lung carcinoma isograft model using A(2B) receptor knockout (A(2B)KO) mice. These mice exhibited significantly attenuated tumor growth and longer survival times after inoculation with Lewis lung carcinoma compared to wild type (WT) controls. Lewis lung carcinoma tumors in A(2B)KO mice contained significantly lower levels of vascular endothelial growth factor (VEGF) compared to tumors growing in WT animals. This difference was due to VEGF production by host cells, which comprised 30 +/- 2% of total tumor cell population. Stimulation of adenosine receptors on WT tumor-infiltrating CD45+ immune cells increased VEGF production fivefold, an effect not seen in tumor-associated CD45+ immune cells lacking A(2B) receptors. In contrast, we found no significant difference in VEGF production between CD45- tumor cells isolated from WT and A(2B)KO mice. Thus, our data suggest that tumor cells promote their growth by exploiting A(2B) adenosine receptor-dependent regulation of VEGF in host immune cells.
Ryzhov
Sergey
S
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Novitskiy
Sergey V
SV
Zaynagetdinov
Rinat
R
Goldstein
Anna E
AE
Carbone
David P
DP
Biaggioni
Italo
I
Dikov
Mikhail M
MM
Feoktistov
Igor
I
D000818:Animals; D018827:Carcinoma, Lewis Lung; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse