The critical role of the Wnt pathway inhibition in sustaining the onset of bone lesions
has been demonstrated in a variety of bone diseases and tumors, and it has been associated
with cancer aggressiveness. We have previously demonstrated that neuroblastoma cells
express Dickkopf 1 (Dkk1), an inhibitor of the canonical Wnt pathway which prevents
the differentiation of bone-forming cells. Since Dkk1 is a secreted factor, it could
have potential clinical application as tumor marker for detecting bone metastasis
and monitoring of disease. In this study, we investigated the diagnostic and prognostic
value of Dkk1 plasma levels in 92 children affected by neuroblastoma, including 32
with bone metastases. Fifty-seven children hospitalized for minor surgical problems
served as control group. Circulating levels of Dkk1 were higher in healthy children
than in normal adults and were comparable to those found in adult patients with aggressive
tumors. No significant differences were found between neuroblastoma patients and controls
and between patients with and without bone metastases. However, when only patients
with metastatic neuroblastoma were considered, the highest Dkk1 levels were detected
in patients that poorly responded to induction chemotherapy and in subjects with unamplified
MYCN and three or more different metastatic sites. The 'Receiver Operating Characteristic'
curve enabled us to identify a threshold value to distinguish patients who were unresponsive
to induction treatment. The relationship between Dkk1 and drug resistance was supported
by in vitro experiments, since an increased sensitivity to doxorubicin was found in
neuroblastoma cells releasing low Dkk1 levels, either constitutively or experimentally
following the treatment with specific siRNA. In conclusion, Dkk1 is released by neuroblastoma
cells and is able to affect the balance between osteoblastogenesis and osteoclastogenesis,
thus favoring the onset of osteolytic metastases. Nevertheless, Dkk1 plasma levels
do not allow the detection of bone lesions in neuroblastoma but seem to have a predictive
value with regard to the severity and the prognosis of the disease in a subset of
patients with metastatic tumor. New knowledge on the biological role of Dkk1 in driving
the natural history of neuroblastoma has to be further investigated and could help
to establish specific therapeutic strategies able to target key factors of tumor progression.
Copyright © 2010 Elsevier Inc. All rights reserved.