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

Prostate. 2008 Sep 15;68(13):1396-404. doi: 10.1002/pros.20805.

Abstract

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 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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Biopsy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary
  • Disease Progression
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Kaplan-Meier Estimate
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Neoplasm Metastasis*
  • Prognosis
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Retrospective Studies
  • Soft Tissue Neoplasms / secondary
  • Tissue Array Analysis
  • beta Catenin / metabolism

Substances

  • Biomarkers, Tumor
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • beta Catenin