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

Abstract

Purpose: Adenosine is a ubiquitous nucleoside that accumulates at high levels in hypoxic regions of solid tumors, and A 3 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 3 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 immunohistochemical 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.

A Gene Expression Profile of Peripheral Blood in Colorectal Cancer

“…The transcripts of 14 genes were identified as being correlated with the incidence of tumor tissues and were associated with clinical outcomes in a microarray study [21] . Two genes with elevated expression in colon cancer patients [22][23] , encoding the A3 adenosine receptor and CCSP-2, were also assayed at the beginning of our study. Since the measurement of a higher cycle number (i.e., Ct greater than 30) generally implies lower amplification efficiency [24] , 15 genes were used for further analysis (Table 2) after eliminating genes with low amplification efficiencies.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…The A2A adenosine receptor (A2AR) is highly expressed in the majority of immune cells. Stimulation leads to inhibition of T-cell and NKT cell proliferation, cytokine production, and proliferation of Tregs and MDSCs (39)(40)(41). Adenosine inhibitors are being tested in the clinic in combination with checkpoint inhibitors in colorectal cancer.…”

Coumarins and adenosine receptors: New perceptions in structure–affinity relationships

“…Melting points (mp) were determined using a Reichert Kofler thermopan or a Büchi 510 apparatus and were not corrected. 1 H (250 MHz) and 13 C (63 MHz) NMR spectra were recorded on a Bruker AMX spectrometer, using DMSO-d 6 or CDCl 3 as solvents. Chemical shifts (δ) and coupling constants (J) were expressed in ppm and in Hz, respectively.…”

“…1 6.91 (td, 1H, H-4′, J = 1.5, 7.9), 6.99 (dd, 1H, H-3′, J = 1.5, 7.9), 7.03-7.12 (m, 2H, H-5, H-5′), 7.22 (dd, 1H, H-7, J = 3.0, 9.1), 7.33 (d, 1H, H-8, J = 9.1), 8 (24).…”

“…[4] Pharmacological modulation of AR pathways opens a new window for drug treatment of a variety of pathologies, such as asthma, neurodegenerative disorders, cancer, inflammatory and ischaemicrelated diseases. [5][6][7][8][9] Coumarins are naturally occurring heterocyclic compounds with an in-depth history in Medicinal Chemistry, [10] as they have been exploited in quite more projects aiming to find, for instance, anticancer, antioxidant, antiinflammatory, antimicrobial and antiviral agents. [11] Although benzopyran is considered a privileged structure, few studies have been addressed towards its application in the discovery of new AR ligands.…”