Purinergic Modulation and CD39/ENTPD1 in Cancer
Pp. 229-292 (64)
Lili Feng, Elliot B. Tapper, Xiaofeng Sun, Marina Gehring, Simon C. Robson and Yan Wu
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.
Adenosine, adjunctive therapy, ATP, cancer therapy, CD39, CD73,
ectonucleotidases, purine-based drugs.
Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Rm601, Boston, MA 02215, USA.