Cell type- and tissue-specific functions of ecto-5′-nucleotidase (CD73)

Abstract

Ecto-5′-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5′-monophosphate to adenosine. Anti-CD73 inhibitory antibodies are currently undergoing clinical testing for cancer immunotherapy. However, many protective physiological functions of CD73 need to be taken into account for new targeted therapies. This review examines CD73 functions in multiple organ systems and cell types, with a particular focus on novel findings from the last 5 years. Missense loss-of-function mutations in the CD73-encoding gene NT5E cause the rare disease “arterial calcifications due to deficiency of CD73.” Aside from direct human disease involvement, cellular and animal model studies have revealed key functions of CD73 in tissue homeostasis and pathology across multiple organ systems. In the context of the central nervous system, CD73 is antinociceptive and protects against inflammatory damage, while also contributing to age-dependent decline in cortical plasticity. CD73 preserves barrier function in multiple tissues, a role that is most evident in the respiratory system, where it inhibits endothelial permeability in an adenosine-dependent manner. CD73 has important cardioprotective functions during myocardial infarction and heart failure. Under ischemia-reperfusion injury conditions, rapid and sustained induction of CD73 confers protection in the liver and kidney. In some cases, the mechanism by which CD73 mediates tissue injury is less clear. For example, CD73 has a promoting role in liver fibrosis but is protective in lung fibrosis. Future studies that integrate CD73 regulation and function at the cellular level with physiological responses will improve its utility as a disease target.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Consistent with this, CD73 is upregulated in cancer cells of triple-negative breast cancer (TNBC), which are tumors characterized by a gene expression signature similar to basal/myoepithelial cells (36,177,178). Accordingly, studies that reconcile tissue-and cell-specific roles for CD73 in normal GI tissues may help better understand CD73 in GI cancers (179,180). Similar to endometrial cancer (175), CD73 is downregulated in cancer cells of bladder and prostate tumors and associates with poor prognosis (181,182).…”

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

“…PABPC1 can combine with adenylate-rich sequences in mRNA under the action of high a nity, which plays an important role in post-transcriptional regulation of genes and is also involved in many metabolic pathways of mRNA, including adenylate polymerization/adenylation, mRNA transport, mRNA translation, microRNA degradation related regulation [45]. NT5E is a ubiquitously expressed glycosylphatidylinositol-xed glycoprotein, which can convert extracellular adenosine 5'-monophosphate to adenosine, and promote tumor development by inhibiting the anti-tumor immune response and promoting angiogenesis [46,47].…”

CD73, Tumor Plasticity and Immune Evasion in Solid Cancers

“…Cluster of differentiation 73 (CD73; encoded by NT5E [ecto-5′-nucleotidase]) molecule is a membrane-bound ecto-5′-nucleotidase ubiquitously expressed throughout the body [ 10 ] and is the major enzyme responsible for the generation of extracellular adenosine (eADO) via enzymatic dephosphorylation of nucleotide adenosine 5′-monophosphate (AMP) [ 11 ]. Other AMP-hydrolyzing enzymes can also be involved in the generation of eADO such as CD39 and ectonucleotide phosphodiesterase 1 (ENPP1), which have been covered by other excellent reviews [ 12 , 13 ].…”