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.