Bv8 regulates myeloid-cell-dependent tumour angiogenesis.
Bone-marrow-derived cells facilitate tumour angiogenesis, but the molecular mechanisms of this facilitation are incompletely understood. We have previously shown that the related EG-VEGF and Bv8 proteins, also known as prokineticin 1 (Prok1) and prokineticin 2 (Prok2), promote both tissue-specific angiogenesis and haematopoietic cell mobilization. Unlike EG-VEGF, Bv8 is expressed in the bone marrow. Here we show that implantation of tumour cells in mice resulted in upregulation of Bv8 in CD11b+Gr1+ myeloid cells. We identified granulocyte colony-stimulating factor as a major positive regulator of Bv8 expression. Anti-Bv8 antibodies reduced CD11b+Gr1+ cell mobilization elicited by granulocyte colony-stimulating factor. Adenoviral delivery of Bv8 into tumours was shown to promote angiogenesis. Anti-Bv8 antibodies inhibited growth of several tumours in mice and suppressed angiogenesis. Anti-Bv8 treatment also reduced CD11b+Gr1+ cells, both in peripheral blood and in tumours. The effects of anti-Bv8 antibodies were additive to those of anti-Vegf antibodies or cytotoxic chemotherapy. Thus, Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumour development and also promotes angiogenesis locally.
Shojaei
Farbod
F
Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Wu
Xiumin
X
Zhong
Cuiling
C
Yu
Lanlan
L
Liang
Xiao-Huan
XH
Yao
Jenny
J
Blanchard
Dominique
D
Bais
Carlos
C
Peale
Franklin V
FV
van Bruggen
Nicholas
N
Ho
Calvin
C
Ross
Jed
J
Tan
Martha
M
Carano
Richard A D
RA
Meng
Y Gloria
YG
Ferrara
Napoleone
N
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000906:Antibodies; D000970:Antineoplastic Agents; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor