Purinergic Modulation and CD39/ENTPD1 in Cancer

Multiple, pleiotropic functional traits are acquired by transformed cells during progression to the neoplastic state. These include genomic instability with several defined mutations that are associated with uncontrolled proliferation, resistance to cell death with induction of immortality, altered cellular metabolism, loss/inactivation of tumor suppressor responses, evasion of immune surveillance, induction of angiogenesis with vascular perturbation, and activation of cell invasiveness resulting in metastasis. A better understanding of any overlapping pathogenetic mechanisms underpinning several of these properties would facilitate development of novel and more effective modalities to treat cancer. Dissecting out the molecular basis for these unique properties of malignancy has already resulted in the discovery and development of novel anticancer drugs.

Extracellular nucleotides and nucleosides have been recently identified as crucial signal mediators in the tumor microenvironment and are known to specifically interact with purinergic receptors. These cellular activation processes provoke different intracellular signaling transduction pathways, termed as “purinergic signaling”. Ectonucleotidases, especially those of CD39/ENTPD family, regulate pericellular levels of proinflammatory adenosine 5'-triphosphate (ATP) to ultimately generate antagonistic antiinflammatory nucleosides such as adenosine thereby tightly modulating purinergic signaling. Such regulated cascades of purinergic signaling have been shown to participate in many of the above fundamental pathophysiological processes in the context of inflammation and immune responses within the tumor microenvironment.

In this chapter, we review several purinergic mechanisms involved in cancer. We specifically highlight the discovery and development and the potential uses of drugs targeting ectonucleotidases that would be applicable to cancer therapy. We further discuss recent advances using purinergic modulation in cancer therapy and consider several of the therapeutic obstacles that would need to be overcome.

Keywords: Adenosine, adjunctive therapy, ATP, cancer therapy, CD39, CD73, ectonucleotidases, purine-based drugs.