PCa is the most frequently diagnosed cancer in males, but very often it is not highly invasive. The wide adoption of PSA screening has been proved to increase diagnosis, to induce over treatment, to cause anxiety, treatment adverse events and to reduce the quality of life of patients [20, 21]. For these reasons continuous efforts are made to identify new more reliable markers for the diagnosis and prognosis of PCa other than PSA.
It is well known that aggressive PCa very often causes bone metastases , which are typically characterized by excessive bone formation: highly active osteoblasts form structurally weak and sclerotic bones at high risk of fracture. DKK-1 is a fundamental inhibitor of the Wnt pathway , controlling the formation and activity of osteoblasts, and it is impaired in osteoblastic bone metastases [7, 23].
Recently DKK-1, as a molecule involved in the control of bone formation, has shown to be involved in PCa biology and in its propensity to develop bone metastases . We previously showed that DKK-1 was elevated in sera of PCa patients . DKK-1 was directly produced by PCa cells, whereas normal prostate tissue did not produce this molecule . In the present study, DKK-1 was not significantly higher in PCa patients than in controls, appearing discordant by the above reported data, nevertheless this may be explained by the different origin of the control group. Indeed, now we compared PCa patients to subjects showing an increased PSA with a benign prostatic disease, whereas in the previous study the control group was constituted by healthy subjects . Here we show that DKK-1 is decreased in PCa patients who will develop bone metastases, whereas PSA is not significantly different in these set of patients. These data are consistent with the role of DKK-1 in the control of cancer progression and of bone formation. A recent study by Thudi et al. demonstrated that in PCa over expressing DKK-1 there was an increased in the growth and metastatic activity of PCa cells but a decreased bone formation in bone metastases . These results confirmed previous data showing that DKK-1 expression is an early event in PCa. During PCa progression DKK-1 expression decreases, particularly in advanced bone metastases . These data support a model in which DKK-1 acts as a molecular switch promoting the transition of bone lesions from osteolytic to osteoblastic . The biological functions of DKK-1 in the bone metastatic process and in tumor progression suggest its potential therapeutic role as a target .
DKK-1 did not add significant information to PSA in the early detection of PCa, although the AUROC for DKK-1 and PSA was comparable. This result should be considered despite several limitations of the study, such as the retrospective design, the small number of patients enrolled and the short follow-up, considering the long natural history of PCa. Noteworthy, we showed that DKK-1 was more elevated in patients with negative bioptic finding further developed PCa during follow-up, whereas PSA was not significantly different in these subjects at enrollement. The potential ability of DKK-1 to detect PCa patients with higher risk of progression would add valuable information to the risk stratification in clinical practice. This is particular important in order to increase the ability to predict PCa development; although only 13 patients developed a new cancer during follow up, the ROC analyses showed that DKK-1 performed slightly better than PSA in detecting these patients. Our results confirmed literature data reporting the role of DKK-1 as a potential serological biomarker in different tumors such as gastric cancer , hepatocellular carcinoma [27, 28], non-small cell lung cancer  and gynaecological cancer .
Our findings need to be confirmed in a larger cohort of patients. DKK-1 could be useful in the difficult management of patients with suspicion of harbouring PCa despite a previously negative biopsy. Such patients are a challenge for the urologists: after an initial negative bioptic finding, a further biopsy has shown to be positive in 10-35% of cases .