title: Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate.
abstract: In order to understand why the angiogenesis inhibitor thrombospondin-1 (TSP1) is often, although not always, associated with prostatic tumors, we have investigated its relationship with the testosterone and the vasculature on which both normal and tumorigenic prostatic epithelia depend. In vivo, androgen withdrawal led to increased TSP1 production and decreased vascularization in the normal rat prostate which was reversed by androgen replacement. Androgen repression of TSP1 production occurred at the transcriptional level and was dependent on the presence of the first intron of the TSP1 gene. In an experimental model of prostate tumorigenesis, TSP1, when delivered by admixed stromal fibroblasts, markedly delayed LNCaP tumor growth and limited tumor vascularization. However, prolonged exposure to TSP1 resulted in the growth of tumors secreting high levels of vascular endothelial growth factor in the bloodstream of tumor-bearing animals and tumor growth was no longer sensitive to TSP1 inhibitory effects. Clinical evidence also suggested that prostate carcinomas are able to adapt to escape the antiangiogenic effects of TSP1. In human androgen-dependent localized prostate carcinomas, TSP1 expression was inversely correlated with blood vessel density. Androgen deprivation in patients with hormone-responsive tumors led to increased TSP1 expression and vascular regression. In contrast, despite a sustained expression in the tumor bed, TSP1 was no longer associated with decreased vascularization in hormone-refractory prostate tumors. Overall, these results suggest that the high in situ TSP1 exposure triggered by androgen deprivation in patients with prostate cancer could lead to early tumor resistance. Such patients could benefit from a combination of androgen deprivation and antiangiogenic therapy in order to minimize the induction of such tumor escape.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, Research Unit 403, Laënnec School of Medicine, Lyon, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Colombel
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Filleur
authors.forename: Pierick
authors.initials: P
authors.lastname: Fournier
authors.forename: Carole
authors.initials: C
authors.lastname: Merle
authors.forename: Julien
authors.initials: J
authors.lastname: Guglielmi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Courtin
authors.forename: Armelle
authors.initials: A
authors.lastname: Degeorges
authors.forename: Claire Marie
authors.initials: CM
authors.lastname: Serre
authors.forename: Raymonde
authors.initials: R
authors.lastname: Bouvier
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.forename: Florence
authors.initials: F
authors.lastname: Cabon
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009919:Orchiectomy; D011467:Prostate; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019700:Thrombospondin 1 / Q000187:drug effects / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D000728:Androgens; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A