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 cellconditioned
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.