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Elevated Expression of A₃ Adenosine Receptors in Human Colorectal Cancer Is Reflected in Peripheral Blood Cells

¹ Department of Clinical and Experimental Medicine, Pharmacology Unit and Interdisciplinary Center for the Study of Inflammation and Departments of ² Experimental and Diagnostic Medicine, ³ Biochemistry and Molecular Biology, ⁴ Surgery, Anesthesiology, and Radiology, and ⁵ Gastroenterology, St. Anna Hospital, University of Ferrara, Ferrara, Italy; and ⁶ King Pharmaceuticals, Cary, North Carolina

Purpose: Adenosine is a ubiquitous nucleoside that accumulates at high levels in hypoxic regions of solid tumors, and A₃ 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 A₃ 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 A₃ 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 A₃ receptor was higher in colon carcinomas as compared with normal mucosa originating from the same individuals (P < 0.05). Overexpression of A₃ receptors at the protein level was confirmed by immunohistochemical studies, whereas no changes in A₃ mRNA accumulation in tumors as compared with the corresponding normal tissue were revealed. The overexpression of A₃ 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 A₃ receptors in circulating blood cells returned to normal after surgical resection for colorectal cancer.

Conclusions: This study provides the first evidence that A₃ 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.

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