Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis.
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.
Nozawa
Hiroaki
H
Diabetes and Comprehensive Cancer Centers, University of California, San Francisco, CA 94143, USA.
Chiu
Christopher
C
Hanahan
Douglas
D
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D019707:Receptors, Chemokine / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015415:Biomarkers; D020690:GTPase-Activating Proteins; C503133:Gr-1 protein, mouse; C490620:Ralbp1 protein, mouse; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D020780:Matrix Metalloproteinase 9