BACKGROUND. 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. METHODS. To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. RESULTS. 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 β-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. CONCLUSIONS. 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.
- Prostate cancer
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