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Preoperative Angiopoietin-2 Serum Levels: A Marker of Malignant Potential in Ovarian Neoplasms and Poor Prognosis in Epithelial Ovarian Cancer

Sallinen, Hanna MD*†‡; Heikura, Tommi MSc*; Laidinen, Svetlana DVM*; Kosma, Veli-Matti MD, PhD†§; Heinonen, Seppo MD, PhD†‡; Ylä-Herttuala, Seppo MD, PhD*; Anttila, Maarit MD, PhD*†‡

International Journal of Gynecological Cancer: December 2010 - Volume 20 - Issue 9 - p 1498-1505
doi: 10.1111/IGC.0b013e3181f936e3
Ovarian Cancer

Introduction: The aims of the study were to explore the levels of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in patients with benign, borderline, or malignant epithelial ovarian tumors and to compare them to those of healthy controls. In addition, we aimed to study how Ang-1 and Ang-2 levels predict the clinical course and survival of patients with epithelial ovarian cancer.

Methods: We enrolled 150 patients with ovarian neoplasms and 34 women with healthy ovaries in this study. Furthermore, we measured the levels of Ang-1 and Ang-2 in patients having an ovarian metastasis or another cancer (n = 29). Serum samples were collected preoperatively at the time of diagnosis, and Ang-1 and Ang-2 levels were measured with an enzyme-linked immunosorbent assay.

Results: Angiopoietin-1 and Ang-2 levels were significantly elevated in serum samples of patients with ovarian carcinoma compared with healthy controls (P = 0.0005 and P < 0.0005, respectively). In addition, Ang-2 levels were significantly higher in patients with ovarian carcinoma compared with patients with benign (P < 0.0005) or borderline ovarian tumors (P = 0.011). In receiver operating characteristic analysis, the area under the curve for serum Ang-2 (0.77) was greater than Ang-1 (0.60) but lower than for cancer antigen 125 (0.95) to differentiate ovarian cancer from healthy control. High serum levels of Ang-1 and Ang-2 were associated with primary residual tumor more than 1 cm after debulking surgery, and high Ang-2 levels correlated positively with an advanced tumor stage (P = 0.042). Elevated Ang-2 level (>2.7 ng/mL) was a significant predictor of poor overall and recurrence-free survival (P = 0.043 and P = 0.033, respectively) when assessing Kaplan-Meier curves by a log-rank test.

Conclusions: Patients with ovarian cancer have higher serum levels of angiopoietins than patients with benign or borderline tumors reflecting the increased angiogenesis. These results also suggest that Ang-2 may serve as an angiogenic marker of decreased patient survival in ovarian cancer.

*Department of Molecular Medicine, A.I.Virtanen Institute, †Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland; Departments of ‡Gynaecology and Obstetrics, and §Pathology, Kuopio University Hospital, Kuopio, Finland.

Received June 13, 2010, and in revised form August 22, 2010.

Accepted for publication August 25, 2010.

Address correspondence and reprint requests to Maarit Anttila, MD, PhD, Department of Gynaecology and Obstetrics, Kuopio University Hospital, PO Box 1777, Kuopio, FIN-70211, Finland. E-mail:

This study was supported by the Finnish Academy, Kuopio University Hospital (EVO grant 5185), Finnish Cultural Foundation, Finnish Cultural Foundation of Northern Savo, Foundation of Kuopio University, and Cancer Foundation of Northern Savo.

We disclose any funding received for this work from the National Institutes of Health and Wellcome Trust or Howard Hughes Medical Institute.

Copyright © 2010 by IGCS and ESGO