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¹ Department of Urology and ² Second Department of Pathology, Yokohama City University Graduate School of Medicine; and ³ Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan

Requests for reprints: Hiroji Uemura, Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Phone: 81-45-787-2679; Fax: 81-45-786-5775. E-mail: hu0428{at}med.yokohama-cu.ac.jp

We showed previously that angiotensin II activated the proliferation of prostate cancer cells and that angiotensin II receptor blockers (ARB) could inhibit it. Here, we investigated whether angiotensin II exerts mitogenic effects on the cross-talk between stromal and cancer cells and whether an ARB can inhibit tumor growth through actions on stromal cells. Cell proliferation and interleukin-6 secretion of prostate stromal PrSC cells stimulated with angiotensin II, tumor necrosis factor-, or epidermal growth factor were examined in the absence and presence of ARB. We examined the effect of ARB on mitogen-activated protein kinase (MAPK) phosphorylation of PrSC and PC-3 cells treated with conditioned medium of PrSC cells and determined the effect of ARB on tumor growth induced by paracrine factors from PrSC cells. Angiotensin II activated the cell proliferation and interleukin-6 secretion of PrSC cells, and ARB inhibited it. Angiotensin II, tumor necrosis factor-, or epidermal growth factor induced MAPK phosphorylation in PrSC cells, and this phosphorylation was inhibited by ARB. Conditioned medium of PrSC cells with angiotensin II activated MAPK phosphorylation in PC-3 cells, and ARB-treated conditioned medium of PrSC cells inhibited it. The tumor growth and angiogenesis of a mixture of PC-3 with PrSC were inhibited by ARB administration, whereas those of PC-3 xenografts were not inhibited. ARB exerted an antiproliferative effect on prostate cancer through paracrine factors from stromal cells. Because prostate stromal cells are thought to be involved in the initiation and development of prostate cancer, the present data suggest the possibility that ARBs are a novel therapeutic class of agents for prostate cancer.

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Received 11/ 3/04; revised 8/13/05; accepted 8/30/05.