Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas.
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.
Doll
Jennifer A
JA
Department of Pathology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, Illinois, 60611, USA.
Stellmach
Veronica M
VM
Bouck
Noël P
NP
Bergh
Anders R J
AR
Lee
Chung
C
Abramson
Lisa P
LP
Cornwell
Mona L
ML
Pins
Michael R
MR
Borensztajn
Jayme
J
Crawford
Susan E
SE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000728:Androgens / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000033:anatomy & histology / Q000378:metabolism; D002369:Castration; D003035:Cobalt / Q000378:metabolism; D005136:Eye Proteins; D006801:Humans; D006965:Hyperplasia; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors; D010179:Pancreas / Q000033:anatomy & histology* / Q000098:blood supply*; D011467:Prostate / Q000033:anatomy & histology* / Q000098:blood supply* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099174:Pigment Epithelium-Derived Factor
D000728:Androgens; D020533:Angiogenesis Inhibitors; D003035:Cobalt; D005136:Eye Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C018021:cobaltous chloride