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Transforming Growth Factor-ß Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells

Departments of ¹ Cancer Biology and ² Urologic Surgery and ³ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee

Requests for reprints: Simon W. Hayward, Department of Urologic Surgery, Vanderbilt University Medical Center, A1302 MCN, Nashville, TN 37232-2765. Phone: 615-322-5823; Fax: 615-322-8990; E-mail: simon.hayward{at}vanderbilt.edu.

Transforming growth factor-ß (TGF-ß) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-ß can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-ß generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-ß expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-ß on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1^CAFTD1, BPH1^CAFTD3, and BPH1^CAFTD5. The data show that TGF-ß has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-ß. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-ß. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-ß by blocking Smad3 and p21 nuclear translocation. On TGF-ß stimulation of the tumorigenic sublines, the activated Akt allows the cell to escape cell cycle arrest. The phosphatidylinositol 3-kinase/Akt pathway is also involved in TGF-ß-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-ß signaling show increased invasion with EMT, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-ß can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo. (Cancer Res 2006; 66(16): 8007-16)

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