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Vasculostatin, a proteolytic fragment of Brain Angiogenesis Inhibitor 1, is an antiangiogenic and antitumorigenic factor

Abstract

Brain angiogenesis inhibitor 1 (BAI1) is a transmembrane protein with unknown function expressed primarily in normal but not tumoral brain. The finding of thrombospondin type 1 repeats in its extracellular domain suggested an antiangiogenic function, but the mechanisms by which a transmembrane receptor could inhibit angiogenesis remained unexplained. Here we demonstrate that BAI1 is proteolytically cleaved at a conserved G-protein-coupled receptor proteolytic cleavage site (GPS), releasing its 120 kDa extracellular domain. We named this secreted fragment Vasculostatin as it inhibited migration of endothelial cells in vitro and dramatically reduced in vivo angiogenesis. Both constitutive and doxycycline-induced expression of Vasculostatin elicited dose-dependent suppression of tumor growth and vascular density in mice, implicating Vasculostatin in the regulation of vascular homeostasis and tumor prevention. Generation of a soluble antiangiogenic factor by cleavage of a pre-existing transmembrane protein represents a novel mechanism for regulating vascular homeostasis and preventing tumorigenesis. Modulation of this cleavage or delivery of Vasculostatin may constitute novel treatment modalities for cancer and other diseases of aberrant angiogenesis, especially in the brain.

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Abbreviations

BAI1:

Brain Angiogenesis Inhibitor 1

CM:

conditioned media

BAI1-ECD:

extracellular domain of BAI1

GPS:

G-protein-coupled receptor proteolytic cleavage site

TSP1:

thrombospondin

TSR:

thrombospondin type 1 repeats

vWF:

von Willebrandt factor

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Acknowledgements

We thank Drs L Chung, P Giannakakou, R Hall and R Swerlick for reading the manuscript and members of the Van Meir lab for helpful comments and Dr Y Nakamura for the BAI1 expression vector. This work was supported in part by grants from the NIH (CA86335 and NS41403 to EGVM) and the University Research Council of Emory University.

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Correspondence to Erwin G Van Meir.

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Kaur, B., Brat, D., Devi, N. et al. Vasculostatin, a proteolytic fragment of Brain Angiogenesis Inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24, 3632–3642 (2005). https://doi.org/10.1038/sj.onc.1208317

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Keywords

  • brain angiogenesis inhibitor
  • central nervous system
  • cancer
  • glioma
  • proteolytic cleavage
  • thrombospondin

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