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Prostate tumor progression is mediated by a paracrine TGF-[beta]/Wnt3a signaling axis.
Li, X 1; Placencio, V 1; Iturregui, J M 2,3; Uwamariya, C 1; Sharif-Afshar, A-R 1; Koyama, T 4; Hayward, S W 1; Bhowmick, N A 1
[Article] Oncogene. 27(56):7118-7130, November 27, 2008.

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Transforming growth factor (TGF)-[beta] is an important paracrine factor in tumorigenesis. Ligand binding of the type I and II TGF-[beta] receptors initiate downstream signaling. The role of stromal TGF-[beta] signaling in prostate cancer progression is unknown. In mice, the conditional stromal knockout of the TGF-[beta] type II receptor expression (Tgfbr2fspKO) resulted in the development of prostatic intraepithelial neoplasia and progression to adenocarcinoma with in 7 months. Clinically, we observed a loss of TGF-[beta] receptor type II expression in 69% of human prostate cancer-associated stroma, compared to 15% of stroma associated with benign tissues (n = 140, P-value < 0.0001). To investigate the mechanism of paracrine TGF-[beta] signaling in prostate cancer progression, we compared the effect of the prostatic stromal cells from Tgfbr2fspKO and floxed TGF-[beta] type II receptor Tgfbr2floxE2/floxE2 mice on LNCaP human prostate cancer cells in vitro and tissue recombination xenografts. Induction of LNCaP cell proliferation and tumorigenesis was observed by Tgfbr2fspKO prostate stroma as a result of elevated Wnt3a expression. Neutralizing antibodies to Wnt3a reversed LNCaP tumorigenesis. The TGF-[beta] inhibition of Wnt3a expression was in part through the suppression of Stat3 activity on the Wnt3a promoter. In conclusion, the frequent loss of stromal TGF-[beta] type II receptor expression in human prostate cancer can relieve the paracrine suppression of Wnt3a expression.