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Bv8 regulates myeloid-cell-dependent tumour angiogenesis

Abstract

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.

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Figure 1: Regulation of Bv8 expression in vitro and in vivo.
Figure 2: Expression of Bv8 in tumour-associated myeloid cells, and effects of anti-Bv8 antibodies on tumour growth.
Figure 3: Anti-Bv8 treatment reduces CD11b + Gr1 + cells in the peripheral blood and the tumours.
Figure 4: Bv8 regulates tumour angiogenesis.
Figure 5: Anti-Bv8 has additive effects with anti-Vegf or cytotoxic chemotherapy.

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Acknowledgements

We thank the Flow Cytometry Laboratory and the Animal Care Facility for their help. We express our appreciation to G. Fuh, A. Chuntarapai, K. Schroeder and the Antibody Technology group. We acknowledge S. Beddha for immunohistochemistry. We also thank J. LeCouter and M. Singh for reading the manuscript.

Author Contributions F.S., X.W. and C.Z. contributed equally to this work. F.S. and N.F. wrote the manuscript. F.S., X.W., C.Z., L.Y., X.-H.L., J.Y., D.B., C.B., F.V.P., N.v.B., C.H., J.R., M.T., R.A.D.C., Y.G.M and N.F. performed experiments, designed research and analysed data.

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Correspondence to Napoleone Ferrara.

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Shojaei, F., Wu, X., Zhong, C. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007). https://doi.org/10.1038/nature06348

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