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Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

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 i...

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Autores principales: Koszałka, Patrycja, Gołuńska, Monika, Urban, Aleksandra, Stasiłojć, Grzegorz, Stanisławowski, Marcin, Majewski, Marceli, Składanowski, Andrzej C., Bigda, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786137/
https://www.ncbi.nlm.nih.gov/pubmed/26964090
http://dx.doi.org/10.1371/journal.pone.0151420
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author Koszałka, Patrycja
Gołuńska, Monika
Urban, Aleksandra
Stasiłojć, Grzegorz
Stanisławowski, Marcin
Majewski, Marceli
Składanowski, Andrzej C.
Bigda, Jacek
author_facet Koszałka, Patrycja
Gołuńska, Monika
Urban, Aleksandra
Stasiłojć, Grzegorz
Stanisławowski, Marcin
Majewski, Marceli
Składanowski, Andrzej C.
Bigda, Jacek
author_sort Koszałka, Patrycja
collection PubMed
description 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 A(1), A(2A), and A(3) 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 A(1)AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A(3)AR 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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spelling pubmed-47861372016-03-23 Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration Koszałka, Patrycja Gołuńska, Monika Urban, Aleksandra Stasiłojć, Grzegorz Stanisławowski, Marcin Majewski, Marceli Składanowski, Andrzej C. Bigda, Jacek PLoS One Research Article 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 A(1), A(2A), and A(3) 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 A(1)AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A(3)AR 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. Public Library of Science 2016-03-10 /pmc/articles/PMC4786137/ /pubmed/26964090 http://dx.doi.org/10.1371/journal.pone.0151420 Text en © 2016 Koszałka et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Koszałka, Patrycja
Gołuńska, Monika
Urban, Aleksandra
Stasiłojć, Grzegorz
Stanisławowski, Marcin
Majewski, Marceli
Składanowski, Andrzej C.
Bigda, Jacek
Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title_full Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title_fullStr Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title_full_unstemmed Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title_short Specific Activation of A(3), A(2A) and A(1) Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration
title_sort specific activation of a(3), a(2a) and a(1) adenosine receptors in cd73-knockout mice affects b16f10 melanoma growth, neovascularization, angiogenesis and macrophage infiltration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786137/
https://www.ncbi.nlm.nih.gov/pubmed/26964090
http://dx.doi.org/10.1371/journal.pone.0151420
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