Real-time Imaging of Lymphogenic Metastasis in Orthotopic Human Breast Cancer

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Abstract
Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-β can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-β generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-β expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-β on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1CAFTD1, BPH1CAFTD3, and BPH1CAFTD5. The data show that TGF-β has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-β. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-β. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-β by blocking Smad3 and p21 nuclear translocation. On TGF-β 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-β-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-β 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-β 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)