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PMID: 16891410 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 33 ·2006-08-15 ·Pages 12493-8

Nozawa H, Chiu C, Hanahan D

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.

MeSH Terms
Animals Biomarkers/metabolism GTPase-Activating Proteins/genetics,metabolism Granulocyte Colony-Stimulating Factor/metabolism Humans Islets of Langerhans/pathology,physiology Matrix Metalloproteinase 9/genetics,metabolism Mice Mice, Transgenic Neoplasms/pathology,physiopathology Neovascularization, Pathologic Neutrophil Infiltration Neutrophils/cytology,metabolism Pancreatic Neoplasms/pathology,physiopathology Rats Receptors, Chemokine/metabolism Receptors, Vascular Endothelial Growth Factor/metabolism Vascular Endothelial Growth Factor A/metabolism
Chemicals
Biomarkers GTPase-Activating Proteins Gr-1 protein, mouse Ralbp1 protein, mouse Receptors, Chemokine Vascular Endothelial Growth Factor A Granulocyte Colony-Stimulating Factor Receptors, Vascular Endothelial Growth Factor Matrix Metalloproteinase 9
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Nozawa Hiroaki
Diabetes and Comprehensive Cancer Centers, University of California, San Francisco, CA 94143, USA.
Chiu Christopher
Hanahan Douglas
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0601807103
Published
2006-08-15
Epub
2006-00-04
Pages
12493-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1531646
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0601807103 PMC Full Text View journal details
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