Dikkopf-1 as a Novel Serologic and Prognostic Biomarker for Lung and Esophageal Carcinomas

Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
Cancer Research (Impact Factor: 9.33). 04/2007; 67(6):2517-25. DOI: 10.1158/0008-5472.CAN-06-3369
Source: PubMed


Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.

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Available from: Nobuhisa Ishikawa
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    • "In contrast, DKK1 is reported to be overexpressed in many malignant tissues including breast cancer, lung and esophageal carcinomas, multiple myeloma, hepatocellular carcinoma (HCC), and osteosarcoma [18]–[22]. Moreover, DKK-1 can serve as a novel diagnostic and prognostic biomarker [19], [21], [22] and may have roles in bone metastases of breast and prostatic carcinomas [23], [24]. Therefore, the function and role of DKK-1 in cancer appears to depend on the cancer cell type and the tumor microenvironment. "
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    ABSTRACT: Background Dickkopf-1 (DKK1) is an antagonist of Wnt/β-catenin signaling implicated in tumorigenesis. However, the biological role of DKK1 and β-catenin involved in chondrosarcoma has not been sufficiently investigated. This study was designed to investigate the expression profiles of DKK1 and β-catenin, and to clarify their clinical values in chondrosarcoma. Methods The mRNA and protein levels of DKK1 and β-catenin in fresh chondrosarcoma and the corresponding non-tumor tissues were analyzed by Real-time PCR and Western blot, respectively. The protein expression patterns of DKK1 and β-catenin were investigated by immunohistochemistry. The associations among DKK1 level, β-catenin accumulation, clinicopathological factors and the overall survival were separately evaluated. Results Both DKK1 and β-catenin levels were remarkably elevated in chondrosarcoma compared with the corresponding non-tumor tissues. High DKK1 level and positive β-catenin accumulation in chondrosarcoma specimens were 58.7% and 53.9%, respectively. Elevated DKK1 level significantly correlated with positive β-catenin accumulation, and they were remarkably associated with histological grade and Musculoskeletal Tumor Society stage. Furthermore, DKK1 level and β-catenin accumulation had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that DKK1 level was an independent prognostic factor for overall survival. Conclusions Elevated DKK1 levels associated with β-catenin accumulation play a crucial role in chondrosarcoma. DKK1 can serve as a novel predictor of poor prognosis in patients with chondrosarcoma.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "DKK-1, DKK-2, DKK-3, and DKK-4 contain 2 discrete cysteine-rich domains, in which the positions of 10 cysteine residues are supremely conserved among family members. DKK-1 and DKK-4, but not DKK-2, DKK-3 or Sgy, have been shown to suppress the Wnt-induced secondary axis induction in Xenopus embryos [22,23]. DKK-4 was found to show high specificity for gastric cancer [24]. "
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    ABSTRACT: Background The different expression level of Dickkopf-1 (DKK-1) in different cancers shows that the function of DKK-1 depends on the histological type of the cancer cells and the tissue microenvironment. To our knowledge, the serum expression level of DKK-1 in breast cancer is little known.Methods Blood samples from 125 consecutive patients diagnosed with breast cancer and 53 control subjects from March 2008 to August 2013 were investigated. Serum DKK-1 expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The overall survival (OS) and relapse-free survival (RFS) analyzed by log-rank test, and survival curves were plotted according to Kaplan¿Meier.ResultsThe mean serum level of DKK-1 in patients with breast cancer was 4.99¿±¿1.50 ng/mL, and was significantly higher than that in healthy individuals (1.88¿±¿0.81 ng/mL, P¿<¿0.001). DKK-1 level correlated significantly with TNM stage (P¿=¿0.009), tumor grade (P¿=¿0.02), lymph node metastasis (P¿=¿0.001), and expression of HER2 (P¿=¿0.002). The DKK-1 expression level was classified as high or low in relation to the median value, and patients with breast cancer (n¿=¿125) were divided into a high expression group (n¿=¿63) and a low expression group (n¿=¿62). The Kaplan-Meier method for survival analysis showed that the patients with a high serum DKK-1 level had a poorer OS (48.7% vs. 81.3%, p¿=¿0.01) and RFS (24.3% vs. 71.6%, p¿=¿0.003) than those with a low expression level. The multivariate Cox regression analysis indicated that serum DKK-1 level was independent prognostic factors for OS and RFS.Conclusions Serum DKK-1 level can be used as a noninvasive biomarker for the prognosis of breast cancer.Virtual SlidesThe virtual slide(s) for this article can be found here:
    Full-text · Article · Aug 2014 · Diagnostic Pathology
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    • "DKK1 is a WNT pathway inhibitor that has been shown to be of prognostic significance in diverse tumor entities such as breast cancer, lung cancer, myeloma but also in esophageal carcinoma.[30]–[38] In addition DKK1 was reported to be elevated in the serum of ESC patients[37]. "
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    ABSTRACT: Lymph node metastasis indicates poor prognosis in esophageal cancer. To understand the underlying mechanisms, most studies so far focused on investigating the tumors themselves and/or invaded lymph nodes. However they neglected the potential events within the metastatic niche, which precede invasion. Here we report the first description of these regulations in patients on transcription level. We determined transcriptomic profiles of still metastasis-free regional lymph nodes for two patient groups: patients classified as pN1 (n = 9, metastatic nodes exist) or pN0 (n = 5, no metastatic nodes exist). All investigated lymph nodes, also those from pN1 patients, were still metastasis-free. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients - even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis.
    Full-text · Article · Jul 2014 · PLoS ONE
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