Dysregulation of Dkk-3 expression in benign and malignant prostatic tissue

• Published in: The Prostate Vol. 68; no. 5; pp. 540 - 547
• Main Authors: Zenzmaier, Christoph, Untergasser, Gerold, Hermann, Martin, Dirnhofer, Stephan, Sampson, Natalie, Berger, Peter
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2008
• Subjects: adenovirus; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cells, Cultured; Dickkopf; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; Humans; immunohistochemistry; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Male; prostate; Prostate - metabolism; Prostate - pathology; Prostatic Hyperplasia - metabolism; Prostatic Hyperplasia - pathology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Stromal Cells - metabolism; Stromal Cells - pathology; tissue microarray
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20711

BACKGROUND The Dickkopf (Dkk) family comprises four members Dkk‐1, ‐2, ‐3, and ‐4. Dkk‐3, the most divergent family member, unlike the others does not modulate Wnt signaling. Dkk‐3 is proposed to function as a secreted tumor suppressor since it is downregulated in a number of cancer cells and prostate cancer tissue and thus may be a promising candidate molecule for therapeutic interference. METHODS The in situ tissue localization of Dkk‐3 protein in normal prostate (NP), benign prostatic hyperplasia (BPH), and prostate carcinoma (PCa) was investigated by immunohistochemistry (IHC)/immunofluorescence. In addition, biological function of Dkk‐3 in terms of proliferation and viability was evaluated in primary prostate basal epithelial cells (PrEC), stromal cells (PrSC), and established human PCa cell lines by treatment with recombinant protein or by overexpression. RESULTS Stimulation with purified recombinant protein and overexpression of Dkk‐3 did not significantly alter in vitro cell proliferation in any primary or tumor cell line evaluated. Dkk‐3 was expressed in both the basal and secretory epithelium of NP. In BPH expression was restricted to defined basal cells and was absent in tumor cells of high grade PCa. In contrast to normal prostatic tissue, Dkk‐3 was upregulated in subglandular blood vessels of BPH and in the reactive stroma of PCa tissue. CONCLUSIONS Our results indicate that Dkk‐3 expression in the normal epithelium of the prostate is lost during benign and malignant transformation and differentiation processes. The loss of expression seems to be counterbalanced by upregulation of Dkk‐3 expression in the blood vessels of the remodeled tissue. Prostate 68: 540–547, 2008. © 2008 Wiley‐Liss, Inc.