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

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          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.

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          Most cited references 17

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          Skeletal complications of malignancy.

          The skeleton is the most common organ to be affected by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney possess a special propensity to spread to bone. Breast carcinoma, the most prevalent malignancy, causes the greatest morbidity. Of great clinical importance is the observation that metastatic bone disease may remain confined to the skeleton. In these patients, the decline in quality of life and eventual death is due almost entirely to skeletal complications and their subsequent treatment. Bone pain is the most common complication of metastatic bone disease, resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by bone metastasis may also be related to the rate of bone resorption. Hypercalcemia occurs in 5-10% of all patients with advanced cancer but is most common in patients with breast carcinoma, multiple myeloma, and squamous carcinomas of the lung and other primary sites. Pathologic fractures are a relatively late complication of bone involvement. The clinical courses of breast and prostate carcinoma are relatively long, with a median survival of 2-3 years. For patients with breast carcinoma, good prognostic factors for survival after the development of bone metastases are good histologic grade, positive estrogen receptor status, bone disease at initial presentation, a long disease free interval, and increasing age. In addition, patients with disease that remains confined to the skeleton have a better prognosis than those with subsequent visceral involvement. For patients with prostate carcinoma, adverse prognostic features include poor performance status, involvement of the appendicular skeleton and visceral involvement, whereas for patients with multiple myeloma, the levels of serum beta2-microglobulin and lactate dehydrogenase and the immunologic phenotype are the most important factors. These prognostic factors may be useful in planning the rational use of bisphosphonates in the treatment of advanced cancer.
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            The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.

            Myeloma cells may secrete factors that affect the function of osteoblasts, osteoclasts, or both. We subjected purified plasma cells from the bone marrow of patients with newly diagnosed multiple myeloma and control subjects to oligonucleotide microarray profiling and biochemical and immunohistochemical analyses to identify molecular determinants of osteolytic lesions. We studied 45 control subjects, 36 patients with multiple myeloma in whom focal lesions of bone could not be detected by magnetic resonance imaging (MRI), and 137 patients in whom MRI detected such lesions. Different patterns of expression of 57 of approximately 10,000 genes from purified myeloma cells could be used to distinguish the two groups of patients (P<0.001). Permutation analysis, which adjusts the significance level to account for multiple comparisons in the data sets, showed that 4 of these 57 genes were significantly overexpressed by plasma cells from patients with focal lesions. One of these genes, dickkopf 1 (DKK1), and its corresponding protein (DKK1) were studied in detail because DKK1 is a secreted factor that has been linked to the function of osteoblasts. Immunohistochemical analysis of bone marrow-biopsy specimens showed that only myeloma cells contained detectable DKK1. Elevated DKK1 levels in bone marrow plasma and peripheral blood from patients with multiple myeloma correlated with the gene-expression patterns of DKK1 and were associated with the presence of focal bone lesions. Recombinant human DKK1 or bone marrow serum containing an elevated level of DKK1 inhibited the differentiation of osteoblast precursor cells in vitro. The production of DKK1, an inhibitor of osteoblast differentiation, by myeloma cells is associated with the presence of lytic bone lesions in patients with multiple myeloma. Copyright 2003 Massachusetts Medical Society
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              Tracking the clonal origin of lethal prostate cancer.

              Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.
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                Author and article information

                Contributors
                tilman.rachner@uniklinikum-dresden.de
                stefanie.thiele@uniklinikum-dresden.de
                andy.goebel@uniklinikum-dresden.de
                andrew.browne@uniklinikum-dresden.de
                susanne.fuessel@uniklinikum-dresden.de
                kati.erdmann@uniklinikum-dresden.de
                manfred.wirth@uniklinikum-dresden.de
                michael.froehner@uniklinikum-dresden.de
                ttodenhoefer@gmail.com
                michael.muders@uniklinikum-dresden.de
                matthias.kieslinger@helmholtz-muenchen.de
                martina.rauner@uniklinikum-dresden.de
                lorenz.hofbauer@uniklinikum-dresden.de
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                2 September 2014
                2 September 2014
                2014
                : 14
                : 1
                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
                4843
                10.1186/1471-2407-14-649
                4167148
                25182503
                © Rachner et al.; licensee BioMed Central Ltd. 2014

                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.

                Categories
                Research Article
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                © The Author(s) 2014

                Oncology & Radiotherapy

                dkk-1, prostate cancer, prognosis

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