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Pigment epithelium–derived factor regulates the vasculature and mass of the prostate and pancreas

Abstract

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium–derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

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Figure 1: Generation of PEDF-deficient mice.
Figure 2: Prostatic hyperplasia in PEDF-deficient mice.
Figure 3: PEDF expression and function in prostate cells.
Figure 4: Androgen and hypoxia regulation of PEDF expression in prostate cells.
Figure 5: Treatment of xenograft subcutaneous human tumors with recombinant PEDF.

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Acknowledgements

We thank the Pathology Core Facility of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University for assistance in specimen procurement. This work was supported in part by National Institutes of Health grant CA64329 to S.E.C. and Department of Defense grant DAMD17-99-1-9521 to J.A.D.

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Correspondence to Susan E Crawford.

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Doll, J., Stellmach, V., Bouck, N. et al. Pigment epithelium–derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 9, 774–780 (2003). https://doi.org/10.1038/nm870

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