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Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis

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Abstract

Delta-like ligand 4 (DLL4) is a ligand of the notch pathway. In tumor angiogenesis, DLL4 switches to vascular maturation by providing a negative feedback on VEGFR2 activity. We investigated the expression of DLL4 in the plasma and cancer tissues from breast cancer patients. Plasma samples were collected from 18 women with localized breast cancer, six women with benign breast disease and from six patients with widespread metastatic disease. DLL4 was assessed using ELISA and in cancer tissues using immunohistochemistry. Patients with metastatic breast cancer had significantly higher levels (median 6.7 ± 0.81 ng/ml) compared to patients with localized tumors (median 5.4 ± 0.70 ng/ml) (p = 0.005) and to patients with benign breast disease (median 4.3 ± 0.28) (p = 0.0003). High histology grade was significantly linked with higher plasma DLL4 levels (median 5.59 ± 0.62 vs. 5.12 ± 0.44 ng/ml; p = 0.01). Surgical removal of high-grade breast cancer resulted in significant reduction in DLL4 plasma levels (p = 0.003). DLL4 was expressed in tumor-associated vessels and in cancer cells. The ratio of DLL4+/CD31+ vascular density (VD) ranged from 23 to 88 % (median 49 %). High DLL4 cancer cell expression and high DLL4+ VD were significantly linked with nodal involvement (p = 0.004 and 0.01, respectively). Linear regression analysis showed a significant association of DLL4 plasma levels with the percentage of DLL4+ cancer cells (p = 0.03, r = 0.50) and with DLL4+ VD (p = 0.0007, r = 0.60). It is concluded that DLL4 is overexpressed in breast cancer cells and breast cancer vasculature and is linked with nodal and distant metastasis. DLL4 plasma levels measurement can reliably estimate the total DLL4 breast cancer/vasculature activity.

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Acknowledgments

The study was financially supported by the Tumor and Angiogenesis Research Group.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Obstetrics/Gynecology, Democritus University of Thrace, 68100, Alexandroupolis, Greece

    Emmanuel Kontomanolis, Vassilios Limberis & Georgios Galazios

  2. Tumour and Angiogenesis Research Group, Department of Radiotherapy/Oncology, Democritus University of Thrace, 68100, Alexandroupolis, Greece

    Marianthi Panteliadou, Stamatia Pouliliou & Michael I. Koukourakis

  3. Department of Pathology, Democritus University of Thrace, 68100, Alexandroupolis, Greece

    Alexandra Giatromanolaki & Efthimios Sivridis

  4. Department of Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece

    Eleni Efremidou

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  1. Emmanuel Kontomanolis
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  2. Marianthi Panteliadou
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  3. Alexandra Giatromanolaki
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  4. Stamatia Pouliliou
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  5. Eleni Efremidou
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  6. Vassilios Limberis
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  7. Georgios Galazios
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  8. Efthimios Sivridis
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  9. Michael I. Koukourakis
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Correspondence to Michael I. Koukourakis.

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For the ‘Tumor and Angiogenesis Research Group’.

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Kontomanolis, E., Panteliadou, M., Giatromanolaki, A. et al. Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis. Med Oncol 31, 945 (2014). https://doi.org/10.1007/s12032-014-0945-0

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  • DOI: https://doi.org/10.1007/s12032-014-0945-0

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