title: Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation.
abstract: Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.
authors.affiliation: Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Fitchev
authors.forename: Susan M
authors.initials: SM
authors.lastname: Wcislak
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.forename: Charles B
authors.initials: CB
authors.lastname: Brendler
authors.forename: Veronica M
authors.initials: VM
authors.lastname: Stellmach
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Mavroudis
authors.forename: Mona L
authors.initials: ML
authors.lastname: Cornwell
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doll
mesh_terms: D000728:Androgens / Q000172:deficiency*; D000818:Animals; D002277:Carcinoma / Q000503:physiopathology; D002460:Cell Line; D013196:Dihydrotestosterone; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D009919:Orchiectomy; D010641:Phenotype; D011467:Prostate / Q000473:pathology / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000503:physiopathology; D017154:Stromal Cells / Q000502:physiology; D019700:Thrombospondin 1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000728:Androgens; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D013196:Dihydrotestosterone
references.citation: Expert Opin Ther Targets. 2009 Feb;13(2):227-34
references.pmid: 19236240
references.citation: Expert Opin Ther Targets. 2009 Feb;13(2):219-25
references.pmid: 19236239
references.citation: Science. 1988 Dec 9;242(4884):1412-5
references.pmid: 2849206
references.citation: J Endocrinol. 2008 Jan;196(1):11-9
references.pmid: 18180313
references.citation: Endocrinology. 1998 Feb;139(2):451-6
references.pmid: 9449610
references.citation: Clin Cancer Res. 1997 Dec;3(12 Pt 1):2507-11
references.pmid: 9815654
references.citation: Endocrinology. 1998 Nov;139(11):4672-8
references.pmid: 9794479
references.citation: Urol Res. 1999 Jun;27(3):174-9
references.pmid: 10422818
references.citation: Cell Death Differ. 2005 Jun;12(6):649-58
references.pmid: 15818399
references.citation: Cell. 1998 Jun 26;93(7):1159-70
references.pmid: 9657149
references.citation: J Cell Biochem. 2001;81(3):437-44
references.pmid: 11255226
references.citation: Cancer. 1997 Feb 15;79(4):772-9
references.pmid: 9024715
references.citation: Prostate. 1997 Sep 15;33(1):38-45
references.pmid: 9294625
references.citation: Prostate. 2007 Feb 15;67(3):255-67
references.pmid: 17192876
references.citation: Endocrinology. 2004 Oct;145(10):4507-12
references.pmid: 15231711
references.citation: Int J Mol Med. 2005 Jan;15(1):49-56
references.pmid: 15583827
references.citation: Cell Mol Life Sci. 2008 Mar;65(5):700-12
references.pmid: 18193162
references.citation: Cancer Gene Ther. 2000 Dec;7(12):1537-42
references.pmid: 11228532
references.citation: J Biol Chem. 1994 Oct 28;269(43):26783-8
references.pmid: 7929414
references.citation: Endocrinology. 1991 Dec;129(6):3187-99
references.pmid: 1954898
references.citation: Biochem Biophys Res Commun. 1998 Oct 9;251(1):287-90
references.pmid: 9790948
references.citation: Clin Cancer Res. 2001 Jan;7(1):81-8
references.pmid: 11205922
references.citation: Endocrinology. 1993 Jan;132(1):169-78
references.pmid: 8419121
references.citation: Nat Med. 2003 Jun;9(6):774-80
references.pmid: 12740569
references.citation: BJU Int. 2002 Feb;89(3):303-9
references.pmid: 11856116
references.citation: Prostate. 1998 Aug 1;36(3):201-6
references.pmid: 9687993
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624-8
references.pmid: 1697685
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10820-5
references.pmid: 9724788
references.citation: Cancer Res. 2005 Jan 1;65(1):300-8
references.pmid: 15665307
references.citation: Am J Pathol. 1999 Sep;155(3):841-51
references.pmid: 10487979
references.citation: J Cell Physiol. 1996 Jan;166(1):231-9
references.pmid: 8557772
references.citation: Prostate. 2001 Dec 1;49(4):293-305
references.pmid: 11746276
references.citation: Prostate. 2003 Sep 15;57(1):57-65
references.pmid: 12886524
references.citation: Urol Res. 1997;25(5):309-14
references.pmid: 9373910
references.citation: Eur Urol. 1996;30(2):191-200
references.pmid: 8875200
references.citation: J Cell Biol. 1993 Jul;122(2):497-511
references.pmid: 7686555
references.citation: Prostate. 1999 Mar 1;38(4):268-77
references.pmid: 10075006
references.citation: J Clin Invest. 1998 Mar 1;101(5):982-92
references.pmid: 9486968
references.citation: Cancer. 1999 Apr 15;85(8):1822-7
references.pmid: 10223578