Abstract
Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cell-conditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment.
Highlights
We show that the expression level of stromal Dkk-3 is relevant to prostate cancer, and we identify two secreted proteins, TGFBI (Transforming Growth Factor Beta Induced) and extracellular matrix protein-1 (ECM-1), whose levels are differentially affected by DKK3 silencing in prostate stromal cells and that appear to play opposing roles in prostate cancer
Changes in the expression of Dkk-3 have been reported in benign prostatic hyperplasia [10], but less is known about the expression of Dkk-3 in cancer stroma
Our observations indicate that DKK3 silencing has cell-type-specific effects in RWPE-1 and WPMY-1 cells that reflect alterations in the stem/progenitor cell phenotype of RWPE-1 cells and, in part, on transforming growth factor–β (TGF-β) signaling in WPMY-1 cells
Summary
Prostate glands of Dkk mutant mice exhibit changes in prostate tissue organization and increased prostate epithelial cell proliferation, suggesting that Dkk-3 is required to maintain a normal microenvironment and that its loss could play a role in cancer progression [4, 7]. Knockdown of Dkk-3 in primary prostate smooth muscle cells reduces their proliferation and differentiation [10]. It is not known if stromal Dkk-3 plays a protective or tumorpromoting role in prostate disease. Dkk-3 is upregulated in the tumor endothelium, suggesting it plays a role in angiogenesis [11,12,13]
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