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

Abstract

Transforming growth factor-B (TGF-B) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-B can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-B generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-B expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-B on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1 CAFTD 1, BPH1 CAFTD 3, and BPH1 CAFTD 5. The data show that TGF-B has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-B. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-B. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-B by blocking Smad3 and p21 nuclear translocation. On TGF-B 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-B-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-B 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-B 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)

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

“…A change in the cellular response to TGF-b is frequently observed in cancer, and there is great interest in the molecular mechanisms responsible for the switch of TGF-b signalling from tumor suppression to tumor promotion (Bierie and Moses, 2006;Inman, 2011). TGF-b1 inhibits proliferation of RWPE-1 cells and BPH-1 benign prostate epithelial cells (Ao et al, 2006), but does not affect proliferation of metastatic PC3 cells or transformed derivatives of BPH-1, where instead it promotes an epithelial-to-mesenchymal transition (Ao et al, 2006;Zhang et al, 2009). An important TGF-b target gene, PMEPA1, has been implicated in this TGF-b switch (Singha et al, 2010), and silencing of PMEPA1 has been shown to reduce RWPE-1 cell proliferation (Liu et al, 2011).…”

PI3K, Erk Signaling in BMP7-Induced Epithelial-Mesenchymal Transition (EMT) of PC-3 Prostate Cancer Cells in 2- and 3-Dimensional Cultures

“…There are reports of EMT induction to other human prostate epithelial cells. For example, tumorigenic sublines of BPH-1 but not the parental non-malignant BPH-1 line could be induced to undergo EMT upon stimulation by TGF-β [37]. Nonmalignant BPH-1 cells with over-expression of snail, however, were shown to assume EMT and invasive phenotype in 3D cultures [38].…”

Cross-talk between Paracrine-Acting Cytokine and Chemokine Pathways Promotes Malignancy in Benign Human Prostatic Epithelium

“…However, as cancer progresses, TGF-h takes on a tumorigenic role, inducing angiogenesis, suppressing apoptotic activity, or enhancing cell motility (19)(20)(21)(22). Target cells respond to TGF-h through a number of specific downstream signaling pathways.…”