Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression.
The secreted Bv8 protein has been recently characterized as a regulator of myeloid cell mobilization and a neutrophil-derived mediator of tumor angiogenesis in several xenografts, but its role in tumor progression in an endogenous setting was unknown. The rat insulin promoter (RIP)-T-antigen (Tag) is a well characterized transgenic mouse model of multistage pancreatic beta-cell tumorigenesis. Also, the role of neutrophils in RIP-Tag angiogenic switching, as assessed by systemic ablation using anti-Gr1 antibodies at different stages of tumor progression, has been recently described. Here, we show that early treatment of RIP-Tag mice with anti-Bv8 antibodies resulted in a significant reduction in the number of angiogenic islets relative to control antibody-treated mice, implicating Bv8 in the angiogenic switch during neoplasia. Histological analysis showed a significant reduction in vascular surface areas in hyperplastic and angiogenic lesions in pancreatic islets from anti-Bv8-treated mice. Anti-Bv8 treatment also inhibited the mobilization and homing of CD11b+Gr1+ cells to the peripheral blood and the emerging neoplastic lesions. However, anti-Bv8 treatment had no effect on tumor vascularization or burden when initiated at later stages of tumor progression. The stage-dependent efficacy of anti-Bv8 treatment appears remarkably similar to that reported after neutrophil ablation, suggesting that Bv8 is an important mediator of neutrophil-dependent angiogenesis in this transgenic model. In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression.
Shojaei
Farbod
F
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Singh
Mallika
M
Thompson
Jennifer D
JD
Ferrara
Napoleone
N
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D018450:Disease Progression; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D007328:Insulin / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats
D039481:CD11b Antigen; D005768:Gastrointestinal Hormones; D007328:Insulin; D009479:Neuropeptides; C486586:Prok2 protein, mouse