Al Shareef, Zainab;
Kardooni, Hoda;
Murillo-Garzón, Virginia;
Domenici, Giacomo;
Stylianakis, Emmanouil;
Steel, Jennifer H;
Rabano, Miriam;
... Kypta, Robert M; + view all
(2018)
Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1.
Oncogene
, 37
pp. 5305-5324.
10.1038/s41388-018-0294-0.
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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.
| Type: | Article |
|---|---|
| Title: | Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41388-018-0294-0 |
| Publisher version: | https://doi.org/10.1038/s41388-018-0294-0 |
| Language: | English |
| Additional information: | © The Author(s), 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Cancer microenvironment, Extracellular signalling molecules, Prognostic markers |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10177750 |
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