Bv8 regulates myeloid-cell-dependent tumour angiogenesis

Nature. 2007 Dec 6;450(7171):825-31. doi: 10.1038/nature06348.


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.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Gastrointestinal Hormones / antagonists & inhibitors
  • Gastrointestinal Hormones / immunology
  • Gastrointestinal Hormones / metabolism*
  • Gene Expression Regulation / drug effects
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism*
  • Neoplasm Transplantation
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neovascularization, Pathologic* / drug therapy
  • Neuropeptides / antagonists & inhibitors
  • Neuropeptides / immunology
  • Neuropeptides / metabolism*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors


  • Antibodies
  • Antineoplastic Agents
  • Gastrointestinal Hormones
  • Neuropeptides
  • Prok2 protein, mouse
  • Vascular Endothelial Growth Factor A
  • Granulocyte Colony-Stimulating Factor