Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

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...

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Bibliographic Details
Published in:Oncogene 2018-09, Vol.37 (39), p.5305-5324
Main Authors: Al Shareef, Zainab, Kardooni, Hoda, Murillo-Garzón, Virginia, Domenici, Giacomo, Stylianakis, Emmanouil, Steel, Jennifer H, Rabano, Miriam, Gorroño-Etxebarria, Irantzu, Zabalza, Ignacio, Vivanco, Maria dM, Waxman, Jonathan, Kypta, Robert M
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Analysis
Bone morphogenetic proteins
Carcinogenesis
Care and treatment
Cellular signal transduction
Chemokines
Development and progression
Epithelial cells
Extracellular matrix
Extracellular Matrix Proteins - metabolism
Gene expression
Genetic aspects
Health aspects
Humans
Hyperplasia
Intercellular Signaling Peptides and Proteins - metabolism
Male
Matrix protein
Messenger RNA
Prostate cancer
Prostatic hyperplasia
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Recurrence (Disease)
RNA
Secretion
Stromal cells
Transforming Growth Factor beta1 - metabolism
Transforming growth factor-b
Transforming growth factors
Tumor Microenvironment - physiology
Tumor proteins
Tumors
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-018-0294-0