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

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.

• Authors: Elena I Deryugina, Ewa Zajac, Anna Juncker-Jensen, Tatyana A Kupriyanova, Lisa Welter, James P Quigley
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 16 Issue 10 Pg. 771-88 (Oct 2014) ISSN: 1476-5586 [Electronic] United States
• PMID: 25379015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inducing Agents
• TIMP1 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Cell Line, Tumor
• Humans
• Macrophages (enzymology, pathology)
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic
• Neutrophils (metabolism, pathology)
• Prostatic Neoplasms (blood supply, enzymology, pathology)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Tumor Microenvironment (physiology)
• Xenograft Model Antitumor Assays