G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models.
Recent studies suggest that tumor-associated CD11b(+)Gr1(+) myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b(+)Gr1(+) cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1alpha, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b(+)Gr1(+) cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.
Shojaei
Farbod
F
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Wu
Xiumin
X
Qu
Xueping
X
Kowanetz
Marcin
M
Yu
Lanlan
L
Tan
Martha
M
Meng
Y Gloria
YG
Ferrara
Napoleone
N
D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005768:Gastrointestinal Hormones / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000276:immunology*; D009479:Neuropeptides / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
D000912:Antibodies, Neoplasm; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor