One of the mechanisms by which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue, the so-called \#8216;intracrine\#8217; androgen formation, plays an important role in this adaptation. In the present study, we investigated how stromal cells derived from normal prostate and prostate cancer affect adrenal androgen DHEA and DHT metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on PSA promoter activity and the proliferation of LNCaP cells. However, when LNCaP cells were treated with DHEA in the presence of prostate-derived stromal cells, especially PCa-derived stromal cells (PCaSC), stromal cells accelerated DHEA-induced PSA promoter activity via androgen receptor activation. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or DHT from DHEA in stromal cells was involved in this acceleration of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5\#945;-reductase inhibitor dutasteride appears to function not only as 5\#945;-reductase inhibitor but also as 3%9\#946;-hydroxysteroid dehydrogenase inhibitor and as antiandrogen. Taken together, this coculture assay system provides new insights of \#8216;paracrine\#8217; and \#8216;intracrine\#8217; androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3495.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO