Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis.
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.
Department of Obstetrics/Gynecology, Democritus University of Thrace, 68100, Alexandroupolis, Greece.
Emmanuel
E
Kontomanolis
Marianthi
M
Panteliadou
Alexandra
A
Giatromanolaki
Stamatia
S
Pouliliou
Eleni
E
Efremidou
Vassilios
V
Limberis
Georgios
G
Galazios
Efthimios
E
Sivridis
Michael I
MI
Koukourakis
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers / Q000378:metabolism*; D001943:Breast Neoplasms / Q000145:classification / Q000378:metabolism* / Q000556:secondary; D002135:Calcium-Binding Proteins; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018226:Fibroadenoma / Q000378:metabolism* / Q000473:pathology; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins