High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

The Wnt inhibitor Dickkopf-1 (DKK-1) has been linked to the progression of malignant bone disease by impairing osteoblast activity. In addition, there is increasing data to suggest direct tumor promoting effects of DKK-1. The prognostic role of DKK-1 expression in prostate cancer remains unclear.

Methods

A prostate cancer tissue microarray (n = 400) was stained for DKK-1 and DKK-1 serum levels were measured in 80 patients with prostate cancer. The independent prognostic value of DKK-1 expression was assessed using multivariate analyses.

Results

DKK-1 tissue expression was significantly increased in prostate cancer compared to benign disease, but was not correlated with survival. However, high DKK-1 serum levels at the time of the diagnosis were associated with a significantly shorter overall and disease-specific survival. Multivariate analyses defined high serum levels of DKK-1 as an independent prognostic marker in prostate cancer (HR 3.73; 95%CI 1.44-9.66, p = 0.007).

Conclusion

High DKK-1 serum levels are associated with a poor survival in patients with prostate cancer. In light of current clinical trials evaluating the efficacy of anti-DKK-1 antibody therapies in multiple myeloma and solid malignancies, the measurement of DKK-1 in prostate cancer may gain clinical relevance.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2407-14-649) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 13

Record: found
Abstract: found
Article: not found

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma.

P Nanjappa, TERU HIDESHIMA, Rao Prabhala … (2009)

Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)-hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated beta-catenin level while down-regulating nuclear factor-kappaB (NF-kappaB) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth.

0 comments Cited 113 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Increased Dickkopf-1 expression in breast cancer bone metastases

N Voorzanger-Rousselot, D Goehrig, F Journe … (2007)

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.

0 comments Cited 54 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis.

Evan Keller, D Daignault, Graham Hall … (2008)

Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106 +/- 10 vs. 19 +/- 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56 +/- 21 EI) compared to non-neoplastic tissues but was significantly decreased versus primary PCa lesions (P < 0.008). The decline in DKK-1 correlated with a shift of beta-catenin staining from the nucleus to the cytoplasm suggesting possible mechanism for the observed decrease in DKK-1 levels during PCa progression. Within metastatic lesions, DKK-1 expression was least abundant in PCa bone metastases relative to all soft tissue PCa metastatic lesions except lymph node metastases. High DKK-1 expression within PCa metastases was further associated with shorter over-all patient survival. Taken together, these data demonstrate that elevated DKK-1 expression is an early event in PCa and that as PCa progresses DKK-1 expression declines, particularly in advanced bone metastases. The decline of DKK-1 in bone metastases can unmask Wnts' osteoblastic activity. These data support a model in which DKK-1 is a molecular switch that transitions the phenotype of PCa osseous lesions from osteolytic to osteoblastic. (c) 2008 Wiley-Liss, Inc.

0 comments Cited 50 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Tilman D Rachner: tilman.rachner@uniklinikum-dresden.de

Stefanie Thiele: stefanie.thiele@uniklinikum-dresden.de

Andy Göbel: andy.goebel@uniklinikum-dresden.de

Andrew Browne: andrew.browne@uniklinikum-dresden.de

Susanne Fuessel: susanne.fuessel@uniklinikum-dresden.de

Kati Erdmann: kati.erdmann@uniklinikum-dresden.de

Manfred P Wirth: manfred.wirth@uniklinikum-dresden.de

Michael Fröhner: michael.froehner@uniklinikum-dresden.de

Tilman Todenhöfer: ttodenhoefer@gmail.com

Michael H Muders: michael.muders@uniklinikum-dresden.de

Matthias Kieslinger: matthias.kieslinger@helmholtz-muenchen.de

Martina Rauner: martina.rauner@uniklinikum-dresden.de

Lorenz C Hofbauer: lorenz.hofbauer@uniklinikum-dresden.de

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 2 September 2014

Publication date PMC-release: 2 September 2014

Publication date Collection: 2014

Volume: 14

Issue: 1

Electronic Location Identifier: 649

Affiliations

[ ]Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, TU Dresden, Fetscherstr 74, 01307 Dresden, Germany

[ ]Department of Urology, TU Dresden, Fetscherstr 74, 01307 Dresden, Germany

[ ]Department of Urology, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany

[ ]Institute of Pathology, TU Dresden, Fetscherstr 74, 01307 Dresden, Germany

[ ]Institute of Clinical Molecular Genetics and Tumor Genetics, Helmholtz Zentrum München, Marchioninistrasse 25, 81377 Munich, Germany

[ ]Center for Regenerative Therapies Dresden, TU Dresden, Fetscherstr 74, 01307 Dresden, Germany

Article

Publisher ID: 4843

DOI: 10.1186/1471-2407-14-649

PMC ID: 4167148

PubMed ID: 25182503

SO-VID: cd797955-f8d7-45dc-bb61-f105d6b05f95

License:

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 May 2014

Date accepted : 30 August 2014

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: dkk-1,prostate cancer,prognosis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: dkk-1, prostate cancer, prognosis

Comments

Comment on this article

scite_

Cited by 36

See all cited by

Most referenced authors 419

See all reference authors

High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients

Read this article at

Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 13

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma.

Increased Dickkopf-1 expression in breast cancer bone metastases

Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 230

Cited by 36

Most referenced authors 419