Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

Abstract

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.

Keywords: adenosine; cancer; epidemiology; purinergic signaling; schizophrenia.

Figure 1

Perturbations of the adenosine system in schizophrenia and cancer. Overview of the population and biochemical evidence for perturbed adenosine system function in schizophrenia and cancer. Reduced cancer rates in schizophrenia patients despite elevated cancer risk implies some underlying biochemical protective mechanism. Reduced extracellular adenosine availability, and hypouricemia observed in these patients may explain the reduced cancer rates. Generated in Biorender.

Figure 2

ATP and adenosine metabolism and signaling in cancer and schizophrenia. Perturbations in extracellular adenosine generating pathways are implicated in schizophrenia (green arrows) and cancer (red arrows). Differential purinergic (P1 and P2 receptors) receptor expression is reported in schizophrenia and cancer. ADA adenosine deaminase, ADK adenosine kinase, ADO adenosine, ATP adenosine triphosphate, ADP adenosine diphosphate AMP adenosine monophosphate, ENTPD ectonucleoside triphosphate diphosphohydrolases, NT5E ecto-5′nucleotidase. Generated in Biorender.