Adenosine receptors and cancer

Adenosine is a ubiquitous signaling molecule whose physiological functions are mediated by its interaction with four G-protein-coupled receptor subtypes, termed A1, A2A, A2B and A3. As a result of increased metabolic rates, this nucleoside is released from a variety of cells throughout the body in concentrations that can have a profound impact on vasculature and immunoescape. However, as high concentrations of adenosine have been reported in cancer tissues, it also appears to be implicated in the growth of tumors. Thus, full characterisation of the role of adenosine in tumor development, by addressing the question of whether adenosine receptors are present in cancer tissues, and, if so, which receptor subtype mediates its effects in cancer growth, is a vital research goal. To this end, this review focuses on the most relevant aspects of adenosine receptor subtype activation in tumors reported so far. Although all adenosine receptors now have an increasing number of recognised biological roles in tumors, it seems that the A2A and A3 subtypes are the most promising as regards drug development. In particular, activation of A2A receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth. Due to this behavior, the addition of A2A antagonists to cancer immunotherapeutic protocols has been suggested as a way of enhancing tumor immunotherapy. Interestingly, the safety of such compounds has already been demonstrated in trials employing A2A antagonists in the treatment of Parkinson's disease. As for A3 receptors, the effectiveness of their agonists in several animal tumor models has led to the introduction of these molecules into a programme of pre-clinical and clinical trials. Paradoxically, A3 receptor antagonists also appear to be promising candidates in human cancer treatment of regimes. Clearly, research in this still field is still in its infancy, with several important and challenging issues remaining to be addressed, although purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health. This article is part of a Special Issue entitled: “Adenosine Receptors”.

Research Highlights
► Adenosine receptors play contrasting effects in tumor cell growth.
► A3 receptors are overexpressed in cancer tissues and cells.
► A2A antagonists enhance immunotherapy of tumors.
► A3 agonists reduce cancer growth by inhibiting cell proliferation.
► A3 antagonists inhibit cancer development by blocking HIF-1α accumulation.