Abstract
Matrix metalloprotease type 9 (MMP-9) has been functionally implicated in VEGF activation, the induction and maintenance of chronic angiogenesis, and early stage tumor growth in a number of mouse models of cancer. In this article, we have identified two inflammatory cell types that are major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis that unfold in RIP1-Tag2 transgenic mice. MMP-9-expressing neutrophils were predominantly found inside angiogenic islet dysplasias and tumors, whereas MMP-9-expressing macrophages were localized along the periphery of such lesions. Transient depletion of neutrophils significantly suppressed VEGF:VEGF-receptor association, a signature of MMP-9 activity, and markedly reduced the frequency of initial angiogenic switching in dysplasias. Thus infiltrating neutrophils can play a crucial role in activating angiogenesis in a previously quiescent tissue vasculature during the early stages of carcinogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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GTPase-Activating Proteins / genetics
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GTPase-Activating Proteins / metabolism
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Granulocyte Colony-Stimulating Factor / metabolism
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Humans
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Islets of Langerhans / pathology
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Islets of Langerhans / physiology
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Transgenic
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Neoplasms* / pathology
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Neoplasms* / physiopathology
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Neovascularization, Pathologic*
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Neutrophil Infiltration*
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Neutrophils / cytology
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Neutrophils / metabolism*
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / physiopathology
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Rats
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Receptors, Chemokine / metabolism
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Biomarkers
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GTPase-Activating Proteins
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Gr-1 protein, mouse
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Ralbp1 protein, mouse
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Receptors, Chemokine
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Vascular Endothelial Growth Factor A
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Granulocyte Colony-Stimulating Factor
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Receptors, Vascular Endothelial Growth Factor
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Matrix Metalloproteinase 9