Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells

Purpose: Adenosine is a ubiquitous nucleoside that accumulates at high levels in hypoxic regions of solid tumors, and A, adenosine receptors have been recently demonstrated to play a pivotal role in the adenosine-mediated inhibition of tumor cell proliferation. In the present work, we addressed the question of the putative relevance of A, subtypes in colorectal adenocarcinomas. Experimental Design: Seventy-three paired samples of tumor and surrounding peritumoral normal mucosa at a distance of 2 and 10 cm from the tumor and blood samples obtained from a cohort of 30 patients with colorectal cancer were investigated to determine the presence of A(3) receptors by means of binding, immunocytochemistry, and real-time reverse transcription-polymerase chain reaction studies. Results: As measured by receptor binding assays, the density of A(3) receptor was higher in colon carcinomas as compared with normal mucosa originating from the same individuals (P < 0.05). Overexpression of A(3) receptors at the protein level was confirmed by inummohistochemical studies, whereas no changes in A(3) mRNA accumulation in tumors as compared with the corresponding normal tissue were revealed. The overexpression of A(3) receptors in tumors was reflected in peripheral blood cells, where the density was approximately 3-fold higher compared with healthy subjects (P < 0.01). In a cohort of 10 patients studied longitudinally, expression of A(3) receptors in circulating blood cells returned to normal after surgical resection for colorectal cancer. Conclusions: This study provides the first evidence that A(3) receptor plays a role in colon tumorigenesis and, more importantly, can potentially be used as a diagnostic marker or a therapeutic target for colon cancer.