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Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment

Academic Article
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Overview

authors

  • Deryugina, Elena
  • Zajac, E.
  • Juncker-Jensen, A.
  • Kupriyanova, T. A.
  • Welter, L.
  • Quigley, James

publication date

  • October 2014

journal

  • Neoplasia  Journal

abstract

  • 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.

subject areas

  • Angiogenesis Inducing Agents
  • Animals
  • Cell Line, Tumor
  • Humans
  • Macrophages
  • Male
  • Matrix Metalloproteinase 9
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic
  • Neutrophils
  • Prostatic Neoplasms
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays
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Identity

PubMed Central ID

  • PMC4212255

International Standard Serial Number (ISSN)

  • 1522-8002

Digital Object Identifier (DOI)

  • 10.1016/j.neo.2014.08.013

PubMed ID

  • 25379015
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Additional Document Info

start page

  • 771

end page

  • 788

volume

  • 16

issue

  • 10

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