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Cancer Biol Ther. 2013 Sep;14(9):860-8. doi: 10.4161/cbt.25643. Epub 2013 Jul 17.

Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth.

Author information

1
Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA.
2
Anatomic Pathology Department; H. Lee Moffitt Cancer Center; Tampa, FL USA.
3
Translational Research Core; Clinical Pharmacology Lab; H. Lee Moffitt Cancer Center; Tampa, FL USA.
4
Department of Women's Oncology and Experimental Therapeutics; H. Lee Moffitt Cancer Center; Tampa, FL USA.
5
Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA; Thoracic Oncology Department; H. Lee Moffitt Cancer Center; Tampa, FL USA.

Abstract

Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves.

KEYWORDS:

NSCLC; SCH58261; ZM241385; adenosine A2A receptor; cancer associated fibroblasts; cell death; tumor microenvironment

PMID:
23917542
PMCID:
PMC3909555
DOI:
10.4161/cbt.25643
[Indexed for MEDLINE]
Free PMC Article

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