Elevated levels of Dickkopf-related protein 3 in seminal plasma of prostate cancer patients

Abstract

BackgroundExpression of Dkk-3, a secreted putative tumor suppressor, is altered in age-related proliferative disorders of the human prostate. We now investigated the suitability of Dkk-3 as a diagnostic biomarker for prostate cancer (PCa) in seminal plasma (SP).MethodsSP samples were obtained from 81 patients prior to TRUS-guided prostate biopsies on the basis of elevated serum prostate-specific antigen (PSA; > 4 ng/mL) levels and/or abnormal digital rectal examination. A sensitive indirect immunoenzymometric assay for Dkk-3 was developed and characterized in detail. SP Dkk-3 and PSA levels were determined and normalized to total SP protein. The diagnostic accuracies of single markers including serum PSA and multivariate models to discriminate patients with positive (N = 40) and negative (N = 41) biopsy findings were investigated.ResultsBiopsy-confirmed PCa showed significantly higher SP Dkk-3 levels (100.9 ± 12.3 vs. 69.2 ± 9.4 fmol/mg; p = 0.026). Diagnostic accuracy (AUC) of SP Dkk-3 levels (0.633) was enhanced in multivariate models by including serum PSA (model A; AUC 0.658) or both, serum and SP PSA levels (model B; AUC 0.710). In a subpopulation with clinical follow-up > 3 years post-biopsy to ensure veracity of negative biopsy status (positive biopsy N = 21; negative biopsy N = 25) AUCs for SP Dkk-3, model A and B increased to 0.667, 0.724 and 0.777, respectively.ConclusionsIn multivariate models to detect PCa, inclusion of SP Dkk-3 levels, which were significantly elevated in biopsy-confirmed PCa patients, improved the diagnostic performance compared with serum PSA only.

Glycogen synthase kinase-3β inhibition depletes the population of prostate cancer stem/progenitor-like cells and attenuates metastatic growth

“…To date, the exact role of Wnt signaling in prostate cancer progression has remained controversial. The observations that various Wnt antagonists like members of the Dickkopf (Dkk) family are highly expressed in osteotropic prostate cancer cells [ 33 ], upregulated in prostate cancer patients [ 34 ] and that stable expression of Dkk-1 stimulates prostate cancer growth [ 35 ] all suggest that decreased Wnt signaling may also be beneficial for metastatic outgrowth.…”

Dickkopf‐related protein 3 promotes pathogenic stromal remodeling in benign prostatic hyperplasia and prostate cancer

“…In the normal prostate, Dkk-3 is predominantly expressed in the epithelial compartment, whereas in the diseased prostate, Dkk-3 is reduced in the epithelial but elevated in the stromal compartment, especially endothelial cells 1 . We recently demonstrated that in patients with PCa seminal plasma Dkk-3 levels are significantly elevated 2 despite the reduced expression of Dkk-3 in secretory epithelial cells 1 , 3 indicating that Dkk-3 derived from tumor neovasculature/stroma is able to diffuse through the diseased tissue into the prostatic fluid while in normal/BPH tissue an intact basement membrane prevents leakage from the stroma to the epithelial compartment and vice versa.…”

Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression

“…To our knowledge, one epidemiological investigation between DKK3 and prostate cancer have been reported. Zenzmaier et al reported that DKK3 levels in seminal plasma were significantly elevated in biopsy-confirmed prostate cancer patients, because loss of expression seems to be counterbalanced by upregulation of DKK3 expression ( 31 ). In this study, we epidemiologically investigated whether SNPs of the DKK3 gene were related to the risk and aggressiveness of prostate cancer for the first time.…”