CD73 on B16F10 melanoma cells in CD73-deficient mice promotes tumor growth, angiogenesis, neovascularization, macrophage infiltration and metastasis

Koszałka, Patrycja; Gołuńska, Monika; Stanisławowski, Marcin; Urbán, A; Stasiłojć, Grzegorz; Majewski, Marceli; Wierzbicki, Piotr M.; Składanowski, Andrzej C.; Bigda, Jacek

doi:10.1016/j.biocel.2015.10.003

Cited by 31 publications

(30 citation statements)

References 43 publications

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“…The CD73-adenosine pathway has gained considerable therapeutic interest in recent years, with mAbs and small-molecule inhibitors targeting CD73 and adenosine receptor inhibitors demonstrating antitumor activity in mouse models of cancer metastasis (4,19,(33)(34)(35)(36). As other studies (4,10,13,15,17) had indicated A2BRi had antitumor activity, we were interested to know whether that activity was directed at A2BR on the tumor or the host.…”

Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro. The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2 þ breast cancer cell lines, and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention. Cancer Res; 76(15); 4372-82. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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“…The adenosine receptor-dependent signaling is used by tumoral cells that overexpress CD73 , to facilitate their immune escape [28, 29]. However, CD73 is also a signaling and an adhesion [17, 18] protein involved in metastasis [30, 31], neovascularization[32] and tumor promotion [33], independently of its immune functions. Its overexpression has already been implicated in the resistance to treatment in vitro [34] and in vivo [33].…”

Section: Discussionmentioning

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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“…CD73 knockout or inhibition/blockade of its activity was demonstrated to restrain the growth of subcutaneous tumors and metastasis formation [ 3 – 5 ]. Its role in tumor progression was reported as multifaceted one, recently including its influence on intratumoral microvessel density [ 1 , 4 , 6 ]. In solid tumors with no adequate blood supply adenosine accumulates and acts as a hypoxia-counteracting mediator initiating a range of tissue responses including regulation of angiogenesis process [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

et al. 2016

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CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine α,β-methylene 5’-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in recently proposed anti-CD73 cancer therapy.

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CD73 on B16F10 melanoma cells in CD73-deficient mice promotes tumor growth, angiogenesis, neovascularization, macrophage infiltration and metastasis

Cited by 31 publications

References 43 publications

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

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

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

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