Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways

Giatromanolaki, Alexandra; Kouroupi, Maria; Pouliliou, Stamatia; Mitrakas, Achilleas; Hasan, Fatma; Pappa, Aglaia; Koukourakis, Michael I.

doi:10.1016/j.lfs.2020.118389

Cited by 42 publications

(31 citation statements)

References 34 publications

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“…Moreover, accumulated evidence suggests the link between CD73 and hypoxia. For instance, high CD73 expression in lung cancer cells is directly linked with hypoxia-inducible factor HIF1α expression by cancer cells [28]; in fulminant acute liver failure [29], CD73 expression can be increased by HIF1α; in gastric cancer, CD73 expression correlates closely with HIF-1α expression [18]. Consistent with these observations, we provided proof of principle data of hypoxia-dependent expression of CD73 in gastric cancer.…”

Section: Discussionsupporting

confidence: 80%

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

et al. 2021

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Background:The Warburg effect is closely associated with malignant phenotypes and poor prognosis in gastric cancer. CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that functions as an oncogene in a variety of human cancers. However, the relationship between CD73 and the Warburg effect has yet to be fully understood. Methods: Integrative analysis was performed to identify glycolysis-related genes in gastric cancer. Loss-of-function and gain-of-function are performed to demonstrate the roles of CD73 in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches are used to uncover the underlying mechanism. Results: In this study, we find that CD73 is a glycolysis-associated gene and is induced by hypoxia in gastric cancer. Genetic silencing of CD73 reduces gastric cancer cell proliferation and glycolytic ability. Opposite effects were observed by CD73 overexpression. Importantly, pharmacological inhibition of CD73 activity by APCP inhibits tumor growth, which can be largely compromised by the addition of adenosine, suggesting an enzyme activity-dependent effect of CD73 in gastric cancer. Furthermore, hijacking tumor glycolysis by 2-DG or galactose largely abrogated the oncogenic roles of CD73, indicating that CD73 promotes tumor growth in a glycolysis-dependent manner in gastric cancer. By the subcutaneous xenograft model, we confirmed the promotive roles of CD73 in regulating cell proliferation and glycolysis in gastric cancer. Conclusions: This study provides strong evidence of the involvement of CD73 in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

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Section: Discussionsupporting

confidence: 80%

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

et al. 2021

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“…Different cell types such as cardiomyocytes, circulating lymphocytes, or cancerassociated fibroblasts in the lung are able to convert ATP to AMP by CD39 followed by AMP conversion to adenosine by CD73 both intra-and extracellularly [29]. Regarding RA, only a few studies exist that describe the fact that regulatory T cells in the synovial fluid express CD73 [30], or M2 macrophages in the blood co-express CD39/CD73 [31].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients

Sohn

Junker

Meurer

et al. 2021

IJMS

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Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.

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“…It has been reported that the increased ectonucleotidase and adenosine are related to hypoxia exposure in many cancer cells (196,197). Remarkably, adenosine drives the overexpression of LDH5, a crucial mediator promoting anaerobic glycolysis, creating a vicious cycle because the large amount of ATP produced by glycolysis feeds the production of adenosine in an ectonucleotidase-rich TME (198). Serra S et al have shown that the A2A adenosine receptor blockade counteracts these effects, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation in vitro studies (197).…”

Section: Aberrant Mitochondrial Biogenesis In Cancer Cells With Immune Cells and Their Effects On The Expressions Of Immune Checkpointsmentioning

confidence: 99%

Section: Aberrant Mitochondrial Biogenesis In Cancer Cells With Immune Cells and Their Effects On The Expressions Of Immune Checkpointsmentioning

confidence: 99%

Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

et al. 2021

Front. Oncol.

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Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

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Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways

Cited by 42 publications

References 34 publications

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients

Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

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