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Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()

According to established notion, one of the major angiogenesis-inducing factors, pro-matrix metalloproteinase-9 (proMMP-9), is supplied to the tumor microenvironment by tumor-associated macrophages (TAMs). Accumulated evidence, however, indicates that tumor-associated neutrophils (TANs) are also cri...

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Autores principales: Deryugina, Elena I., Zajac, Ewa, Juncker-Jensen, Anna, Kupriyanova, Tatyana A., Welter, Lisa, Quigley, James P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212255/
https://www.ncbi.nlm.nih.gov/pubmed/25379015
http://dx.doi.org/10.1016/j.neo.2014.08.013
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author Deryugina, Elena I.
Zajac, Ewa
Juncker-Jensen, Anna
Kupriyanova, Tatyana A.
Welter, Lisa
Quigley, James P.
author_facet Deryugina, Elena I.
Zajac, Ewa
Juncker-Jensen, Anna
Kupriyanova, Tatyana A.
Welter, Lisa
Quigley, James P.
author_sort Deryugina, Elena I.
collection PubMed
description According to established notion, one of the major angiogenesis-inducing factors, pro-matrix metalloproteinase-9 (proMMP-9), is supplied to the tumor microenvironment by tumor-associated macrophages (TAMs). Accumulated evidence, however, indicates that tumor-associated neutrophils (TANs) are also critically important for proMMP-9 delivery, especially at early stages of tumor development. To clarify how much angiogenic proMMP-9 is actually contributed by TAMs and TANs, we quantitatively evaluated TAMs and TANs from different tumor types, including human xenografts and syngeneic murine tumors grown in wild-type and Mmp9-knockout mice. Whereas host MMP-9 competence was required for full angiogenic potential of both normal and tumor-associated leukocytes, direct comparisons of neutrophils versus macrophages and TANs versus TAMs demonstrated that macrophages and TAMs secrete 40- to 50-fold less proMMP-9 than the same numbers of neutrophils or TANs. Correspondingly, the levels of MMP-9–mediated in vivo angiogenesis induced by neutrophils and TANs substantially exceeded those induced by macrophages and TAMs. MMP-9–delivering TANs were also required for development of metastasis-supporting intratumoral vasculature, characterized by ≥ 11-μm size lumens and partial coverage with stabilizing pericytes. Importantly, MMP-9–producing TAMs exhibit M2-skewed phenotype but do not express tissue inhibitor of metalloproteinases-1 (TIMP-1), a novel characteristic allowing them to secrete TIMP-1–free, neutrophil-like MMP-9 zymogen unencumbered by its natural inhibitor. Together, our findings support the notion whereby TANs, capable of immediate release of their pre-stored cargo, are the major contributors of highly angiogenic MMP-9, whereas tumor-influxing precursors of macrophages require time to differentiate, polarize into M2-skewed TAMs, shut down their TIMP-1 expression, and only then, initiate relatively low-level production of TIMP-free MMP-9 zymogen.
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spelling pubmed-42122552014-11-06 Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()() Deryugina, Elena I. Zajac, Ewa Juncker-Jensen, Anna Kupriyanova, Tatyana A. Welter, Lisa Quigley, James P. Neoplasia Article According to established notion, one of the major angiogenesis-inducing factors, pro-matrix metalloproteinase-9 (proMMP-9), is supplied to the tumor microenvironment by tumor-associated macrophages (TAMs). Accumulated evidence, however, indicates that tumor-associated neutrophils (TANs) are also critically important for proMMP-9 delivery, especially at early stages of tumor development. To clarify how much angiogenic proMMP-9 is actually contributed by TAMs and TANs, we quantitatively evaluated TAMs and TANs from different tumor types, including human xenografts and syngeneic murine tumors grown in wild-type and Mmp9-knockout mice. Whereas host MMP-9 competence was required for full angiogenic potential of both normal and tumor-associated leukocytes, direct comparisons of neutrophils versus macrophages and TANs versus TAMs demonstrated that macrophages and TAMs secrete 40- to 50-fold less proMMP-9 than the same numbers of neutrophils or TANs. Correspondingly, the levels of MMP-9–mediated in vivo angiogenesis induced by neutrophils and TANs substantially exceeded those induced by macrophages and TAMs. MMP-9–delivering TANs were also required for development of metastasis-supporting intratumoral vasculature, characterized by ≥ 11-μm size lumens and partial coverage with stabilizing pericytes. Importantly, MMP-9–producing TAMs exhibit M2-skewed phenotype but do not express tissue inhibitor of metalloproteinases-1 (TIMP-1), a novel characteristic allowing them to secrete TIMP-1–free, neutrophil-like MMP-9 zymogen unencumbered by its natural inhibitor. Together, our findings support the notion whereby TANs, capable of immediate release of their pre-stored cargo, are the major contributors of highly angiogenic MMP-9, whereas tumor-influxing precursors of macrophages require time to differentiate, polarize into M2-skewed TAMs, shut down their TIMP-1 expression, and only then, initiate relatively low-level production of TIMP-free MMP-9 zymogen. Neoplasia Press 2014-10-23 /pmc/articles/PMC4212255/ /pubmed/25379015 http://dx.doi.org/10.1016/j.neo.2014.08.013 Text en © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Article
Deryugina, Elena I.
Zajac, Ewa
Juncker-Jensen, Anna
Kupriyanova, Tatyana A.
Welter, Lisa
Quigley, James P.
Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title_full Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title_fullStr Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title_full_unstemmed Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title_short Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment()()
title_sort tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing mmp-9 in the tumor microenvironment()()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212255/
https://www.ncbi.nlm.nih.gov/pubmed/25379015
http://dx.doi.org/10.1016/j.neo.2014.08.013
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