The Roles of CD73 in Cancer

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Abstract

Purinergic signaling has emerged as an important player in cancer progression and is regulated by a series of nucleotidases. Among the enzyme cascade, CD73, which catelyzes AMP breakdown to adenosine, has been found to be overexpressed in many types of cancer. Various factors and mechanisms are employed to regulate expression of CD73. Accumulating studies have shown that CD73 is a key regulatory molecule of cancer cells proliferation, migration and invasion in vitro, tumor angiogenesis, and tumor immune escape in vivo. With such important roles in cancer, CD73 has become an appealing therapy target. Recent evidences in mice models demonstrated that targeted blockade of CD73 could be a favorable therapeutic approach for cancer patients in the future. In this review, we will summarize the multiple roles of CD73 in cancer development, including its clinical significance, its promotive effects on tumor growth, metastasis, and angiogenesis, and its suppressive effects on immune response, regulatory mechanisms of CD73 expression, and current situation of anti-CD73 cancer therapy.

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Most cited references 70

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Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Human health is under constant threat of a wide variety of dangers, both self and nonself. The immune system is occupied with protecting the host against such dangers in order to preserve human health. For that purpose, the immune system is equipped with a diverse array of both cellular and non-cellular effectors that are in continuous communication with each other. The naturally occurring nucleotide adenosine 5'-triphosphate (ATP) and its metabolite adenosine (Ado) probably constitute an intrinsic part of this extensive immunological network through purinergic signaling by their cognate receptors, which are widely expressed throughout the body. This review provides a thorough overview of the effects of ATP and Ado on major immune cell types. The overwhelming evidence indicates that ATP and Ado are important endogenous signaling molecules in immunity and inflammation. Although the role of ATP and Ado during the course of inflammatory and immune responses in vivo appears to be extremely complex, we propose that their immunological role is both interdependent and multifaceted, meaning that the nature of their effects may shift from immunostimulatory to immunoregulatory or vice versa depending on extracellular concentrations as well as on expression patterns of purinergic receptors and ecto-enzymes. Purinergic signaling thus contributes to the fine-tuning of inflammatory and immune responses in such a way that the danger to the host is eliminated efficiently with minimal damage to healthy tissues.

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Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis.

John Stagg, Upulie Divisekera, Nicole McLaughlin … (2010)

Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5'-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Biomed Res Int

Journal ID (iso-abbrev): Biomed Res Int

Journal ID (publisher-id): BMRI

Title: BioMed Research International

Publisher: Hindawi Publishing Corporation

ISSN (Print): 2314-6133

ISSN (Electronic): 2314-6141

Publication date (Print): 2014

Publication date (Electronic): 14 July 2014

Volume: 2014

Electronic Location Identifier: 460654

Affiliations

Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, Shanxi 710038, China

Author notes

*Hui-zhong Zhang: huizz328@ 123456163.com

Academic Editor: Beric Henderson

Article

DOI: 10.1155/2014/460654

PMC ID: 4121992

PubMed ID: 25126561

SO-VID: 968c5b3d-45d6-4730-9d80-3b58a6ecfa99

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 April 2014

Date revision received : 7 July 2014

Date accepted : 8 July 2014

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