High expression of Tie-2 predicts poor prognosis in primary high grade serous ovarian cancer

Abstract

Background: Antiangiogenic therapy, although part of standard treatment in ovarian cancer, has variable efficacy. Furthermore, little is known about the prognostic biomarkers and factors influencing angiogenesis in cancer tissue. We evaluated the expression of angiopoietin-2 and two endothelial tyrosine kinase receptors, Tie-1 and Tie-2, and assessed their value in the prediction of survival in patients with malignant epithelial ovarian cancer. We also compared the expression of these factors between primary high grade serous tumors and their distant metastasis.

Materials and methods: We evaluated 86 women with primary epithelial ovarian cancer. Matched distal omental metastasis were investigated in 18.6% cases (N = 16). The expression levels of angiogenic factors were evaluated by immunohistochemistry in 306 specimens and by qRT-PCR in 111 samples.

Results: A high epithelial expression level of Tie-2 is a significant prognostic factor in primary high grade serous ovarian cancer. It predicted significantly shorter overall survival both in univariate (p<0.001) and multivariate survival analyses (p = 0.022). Low angiopoietin-2 expression levels in primary ovarian tumors were significantly associated with shorter overall survival (p = 0.015) in the univariate survival analysis. A low expression of angiopoietin-2 was also significantly related to high grade tumors, size of residual tumor after primary surgery and the recurrence of cancer (p = 0.008; p = 0.012; p = 0.018) in the whole study population. The expression of angiopoietin-2 and Tie-2 was stronger in distal omental metastasis than in primary high grade serous tumors in matched-pair analysis (p = 0.001; p = 0.002).

Conclusions: The angiogenic factor, angiopoietin-2, and its receptor Tie-2 seem to be significant prognostic factors in primary epithelial ovarian cancer. Their expression levels are also increased in metastatic lesions in comparison with primary tumors.

Fig 1. Immunohistochemical staining scores of primary tumors and metastases.

IRS was calculated from the tumor epithelium of 86 primary ovarian tumors and 16 metastatic lesions (grey dots). Ang-2, Tie-1 and Tie-2 groups include 86 ovarian cancer patients each and Ang-2met, Tie-1met and Tie-2met groups have 16 patients each. Wilcoxon signed-rank test was used to compare the IRS values for primary tumors and related metastases. Significant p-values are marked in the Figure. The median IRS of the group is signed with a black dot. Ang-2 met Angiopoietin-2 metastasis, IRS immunoreactive score.

Fig 2

As compared to the primary tumors, related omental metastases showed stronger expression of Ang-2 (a and b) and Tie-2 (e and f). Primary tumors are shown on the left column and related metastases on the right. The vascular endothelial expression was strong in Ang-2 (black arrow in a). Tie-1 expression did not differ significantly between the primary and the distal metastatic tumors (c and d). Tie-1 was expressed in the tumor stroma (black arrow in d).

Fig 3. Kaplan Maier curves of the immunohistochemical biomarkers as prognostic factors in ovarian cancer patients.

Poor overall survival (OS) was significantly associated with high Tie-2 immunoreactive score (IRS) (a) in the univariate and multivariate analyses of primary high grade serous tumors. Short OS was also associated with low angiopoietin-2 (Ang-2) IRS of all ovarian cancer patients (b). Tie-2 IRS of all histologies and grades together (c) and Ang-2 IRS of only high grade serous tumors (d) did not reach significance.