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Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer

INTRODUCTION: In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recr...

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Autores principales: Bronger, Holger, Kraeft, Sara, Schwarz-Boeger, Ulrike, Cerny, Claudia, Stöckel, Alexandra, Avril, Stefanie, Kiechle, Marion, Schmitt, Manfred
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496148/
https://www.ncbi.nlm.nih.gov/pubmed/22333315
http://dx.doi.org/10.1186/bcr3115
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author Bronger, Holger
Kraeft, Sara
Schwarz-Boeger, Ulrike
Cerny, Claudia
Stöckel, Alexandra
Avril, Stefanie
Kiechle, Marion
Schmitt, Manfred
author_facet Bronger, Holger
Kraeft, Sara
Schwarz-Boeger, Ulrike
Cerny, Claudia
Stöckel, Alexandra
Avril, Stefanie
Kiechle, Marion
Schmitt, Manfred
author_sort Bronger, Holger
collection PubMed
description INTRODUCTION: In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In human breast cancer, CXCL9 mRNA overexpression correlates with the number of tumor infiltrating lymphocytes and predicts response to different chemotherapeutic regimens. Raising the intratumoral CXCR3 ligand concentration is therefore a possible way to enhance immune intervention in breast cancer. Little is known, however, about expression levels and regulation of these chemokines in human breast cancer. Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer. METHODS: CXCL9 was visualized in breast cancer specimens by immunohistochemistry, expression levels of CXCL9 and cyclooxygenases were determined by ELISA and western blotting, respectively. For regulation studies, Michigan Cancer Foundation-7 (MCF-7) and M.D. Anderson - Metastatic Breast 231 (MDA-MB 231) breast cancer cells were stimulated with IFN-γ with or without prostaglandin E(2 )(PGE(2)) or COX inhibitors (indomethacin, acetylsalicylic acid (ASA), celecoxib). CXCR3 ligand release from cells was measured by ELISA. RESULTS: Within the tumor microenvironment, cancer cells are the major source of CXCL9. PGE(2 )impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Otherwise, high concentrations of the Cyclooxygenase-2 (COX-2) specific antagonist celecoxib have opposite effects and impair CXCL9 and CXCL10 release. In human breast cancer tissue specimens there is an inverse correlation between COX-2 overexpression and CXCL9 concentration, suggesting that the observed in vitro effects are of importance in vivo as well. CONCLUSIONS: Suppressing endogenous PGE(2 )synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration. Yet, to this end the unselective COX inhibitors ASA and indomethacin seem preferable to celecoxib that at higher concentrations reduces CXCR3 ligand release most probably due to COX independent mechanisms.
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spelling pubmed-34961482012-11-14 Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer Bronger, Holger Kraeft, Sara Schwarz-Boeger, Ulrike Cerny, Claudia Stöckel, Alexandra Avril, Stefanie Kiechle, Marion Schmitt, Manfred Breast Cancer Res Research Article INTRODUCTION: In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In human breast cancer, CXCL9 mRNA overexpression correlates with the number of tumor infiltrating lymphocytes and predicts response to different chemotherapeutic regimens. Raising the intratumoral CXCR3 ligand concentration is therefore a possible way to enhance immune intervention in breast cancer. Little is known, however, about expression levels and regulation of these chemokines in human breast cancer. Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer. METHODS: CXCL9 was visualized in breast cancer specimens by immunohistochemistry, expression levels of CXCL9 and cyclooxygenases were determined by ELISA and western blotting, respectively. For regulation studies, Michigan Cancer Foundation-7 (MCF-7) and M.D. Anderson - Metastatic Breast 231 (MDA-MB 231) breast cancer cells were stimulated with IFN-γ with or without prostaglandin E(2 )(PGE(2)) or COX inhibitors (indomethacin, acetylsalicylic acid (ASA), celecoxib). CXCR3 ligand release from cells was measured by ELISA. RESULTS: Within the tumor microenvironment, cancer cells are the major source of CXCL9. PGE(2 )impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Otherwise, high concentrations of the Cyclooxygenase-2 (COX-2) specific antagonist celecoxib have opposite effects and impair CXCL9 and CXCL10 release. In human breast cancer tissue specimens there is an inverse correlation between COX-2 overexpression and CXCL9 concentration, suggesting that the observed in vitro effects are of importance in vivo as well. CONCLUSIONS: Suppressing endogenous PGE(2 )synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration. Yet, to this end the unselective COX inhibitors ASA and indomethacin seem preferable to celecoxib that at higher concentrations reduces CXCR3 ligand release most probably due to COX independent mechanisms. BioMed Central 2012 2012-02-14 /pmc/articles/PMC3496148/ /pubmed/22333315 http://dx.doi.org/10.1186/bcr3115 Text en Copyright ©2012 Bronger et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Bronger, Holger
Kraeft, Sara
Schwarz-Boeger, Ulrike
Cerny, Claudia
Stöckel, Alexandra
Avril, Stefanie
Kiechle, Marion
Schmitt, Manfred
Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title_full Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title_fullStr Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title_full_unstemmed Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title_short Modulation of CXCR3 ligand secretion by prostaglandin E(2 )and cyclooxygenase inhibitors in human breast cancer
title_sort modulation of cxcr3 ligand secretion by prostaglandin e(2 )and cyclooxygenase inhibitors in human breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496148/
https://www.ncbi.nlm.nih.gov/pubmed/22333315
http://dx.doi.org/10.1186/bcr3115
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