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Androgens Repress the Expression of the Angiogenesis Inhibitor Thrombospondin-1 in Normal and Neoplastic Prostate

¹ Institut National de la Sante et de la Recherche Medicale, Research Unit 403, Laënnec School of Medicine, Lyon, France; ² 2Centre National de la Recherche Scientifique, UPR 9079, Institut André Lwoff, Villejuif, France; and ³ Departments of Urology and ⁴ Pathology, Edouard Herriot Hospital, Lyon, France

Requests for reprints: F. Cabon, Centre National de la Recherche Scientifique UPR9079, 7 rue Guy Môquet, 94801 Villejuif, France. Phone: 33-14958-3387; Fax: 33-14958-3307; E-mail: fcabon{at}vjf.cnrs.fr.

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.

Key Words: testosterone • TGFß • LNCaP • VEGF • resistance

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