Dual, enzymatic and non-enzymatic, function of ecto-5'-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells.

Sądej, Rafał; Składanowski, Andrzej C.

doi:10.18388/abp.2012_2105

Cited by 76 publications

(81 citation statements)

References 39 publications

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“…Since the CD73 protein was hardly detected on Western blots of HaCaT cells, compared to SQ20B cells, this suggests (i) that an additional post-translational control of CD73 exists in HaCaT cells, and (ii) that most of the CD73 protein is dedicated to enzymatic functions in HaCaT cells. As adhesion is believed to be controlled by the non-enzymatic activity of CD73 [18, 19], we propose that the residual CD73 protein detected in HaCaT cells may play a minor role in cellular adhesion. However, HaCaT cells have a much stronger basal adhesion than SCC61 and SQ20B cells (Supplementary Figure S2), thus indicating that this function mainly relies on a different pathway in this cell line.…”

Section: Resultsmentioning

confidence: 99%

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

et al. 2016

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At the time of diagnosis, 60% of patients with head and neck squamous cell carcinoma (HNSCC) present tumors in an advanced stage (III-IV) of disease and 80% will relapse within the first two years post-treatment, due to their frequent radio(chemo)resistance. To identify new molecular targets and companion biomarkers, we have investigated the miRNome of 75 stage III-IV oropharynx tumors without relapse (R) or with loco-regional relapse (non-responder, NR) within two years post-treatment. Interestingly, miR-422a was significantly downregulated in NR tumors, in agreement with the increase in cell proliferation and adhesion induced by miR-422a inhibition in vitro. Furthermore, we identified CD73/NT5E oncogene as target of miR-422a. Indeed, modulation of the endogenous level of miR-422a inversely influences the expression and the enzymatic activity of CD73. Moreover, knocking down CD73 mimics the effects of miR-422a upregulation. Importantly, in tumors, miR-422a and CD73 expression levels are inversely correlated, and both are predictive of relapse free survival - especially considering loco(regional) recurrence - in vitro two independent cohorts of advanced oropharynx or HNSCC (N=255) tumors. In all, we reported, for the first time, that MiR-422a and its target CD73 are involved in early loco(regional) recurrence of HNSCC tumors and are new targets for personalized medicine.

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Section: Resultsmentioning

confidence: 99%

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

et al. 2016

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“…Putative binding partners of CD73, on cells or in the ECM, remain poorly defined. Sadej et al . have recently demonstrated that CD73 gene‐silencing in melanoma cells reduced migration on tenascin C and that this mechanism was independent of CD73 enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

“…recently demonstrated that both enzymatic and non‐enzymatic functions of CD73 were involved in the aggressive behaviour of cancer cells. The enzymatic functions of CD73 were primarily involved in invasion of tumor cells, whereas non‐enzymatic effects of CD73 contributed to cell adhesion and migration …”

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confidence: 99%

Anti‐CD73 therapy impairs tumor angiogenesis

Allard

Turcotte

Spring

et al. 2013

Intl Journal of Cancer

144

124

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CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.CD73 is a glycosyl-phosphatidylinositol (GPI)-anchored nucleotidase that catalyzes the hydrolysis of extracellular adenosine monophosphates (AMP) into adenosine. CD73 is found overexpressed in several types of cancer, including bladder cancer, leukemia, glioma, glioblastoma, melanoma, ovarian cancer, colon cancer and breast cancer. 1,2 CD73 overexpression in tumors is at least in part a consequence of the hypoxic nature of the tumor microenvironment. Accordingly, CD73 transcription is induced by hypoxia-inducible factor (HIF)21. 3,4 CD73 expression is also upregulated following loss of estrogen receptor (ER) signaling in breast cancer 5 and epigenetically regulated in melanoma 6 and breast cancer cells. 7 Landmark studies by Sitkovsky et al. demonstrated that extracellular adenosine accumulates in tumors and potently suppresses the function of tumor-infiltrating T cells via A2A adenosine receptors. [8][9][10][11] Inspired by this body of work, studies from our laboratory and others have underscored the therapeutic potential of blocking CD73 for cancer therapy. 12-16 Using CD73-deficient mice and targeted CD73 blockade with a monoclonal antibody (mAb), we demonstrated that anti-CD73 therapy can effectively rescue endogenous and treatment-induced anti-tumor immune responses from the suppressive effects of extracellular adenosine. [12][13][14]

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“…In that sense, it is of note that eN functions not only just as the enzyme converting AMP to adenosine, but also as cell adhesion molecule (CD73), implicated in cell-cell and cell-extracellular matrix interactions (Vogel et al 1993;Olmo et al 1992). Specifically, eN establishes highly specific interactions with tenascin C and several other extracellular matrix proteins (Sadej et al 2008), whereas the interactions influence cell adhesion, migration, and adenosine generation (Sadej and Skladanowski, 2012). In support of the view, it has been recently shown that inhibition of metastatic potential in breast tumor cell lines was associated with impairment of cell motility due to a translocation of eN from random membrane distribution to clusters localized in microdomains (Terp et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 and Ecto-5′-Nucleotidase by Rat Cortical Astrocytes In Vitro

et al. 2015

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Extracellular ATP (eATP) acts as a danger-associated molecular pattern which induces reactive response of astrocytes after brain insult, including morphological remodeling of astrocytes, proliferation, chemotaxis, and release of proinflammatory cytokines. The responses induced by eATP are under control of ecto-nucleotidases, which catalyze sequential hydrolysis of ATP to adenosine. In the mammalian brain, ecto-nucleotidases comprise three enzyme families: ecto-nucleoside triphosphate diphosphohydrolases 1-3 (NTPDase1-3), ecto-nucleotide pyrophosphatase/phospodiesterases 1-3 (NPP1-3), and ecto-5'-nucleotidase (eN), which crucially determine ATP/adenosine ratio in the pericellular milieu. Altered expression of ecto-nucleotidases has been demonstrated in several experimental models of human brain dysfunctions. In the present study, we have explored the pattern of NTPDase1-3, NPP1-3, and eN expression by cultured cortical astrocytes challenged with 1 mmol/L ATP (eATP). At the transcriptional level, eATP upregulated expression of NTPDase1, NTPDase2, NPP2, and eN, while, at translational and functional levels, these were paralleled only by the induction of NTPDase2 and eN. Additionally, eATP altered membrane topology of eN, from clusters localized in membrane domains to continuous distribution along the cell membrane. Our results suggest that eATP, by upregulating NTPDase2 and eN and altering the enzyme membrane topology, affects local kinetics of ATP metabolism and signal transduction that may have important roles in the process related to inflammation and reactive gliosis.

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Dual, enzymatic and non-enzymatic, function of ecto-5'-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells.

Cited by 76 publications

References 39 publications

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

Anti‐CD73 therapy impairs tumor angiogenesis

Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 and Ecto-5′-Nucleotidase by Rat Cortical Astrocytes In Vitro

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