Objective: We have previously demonstrated that the receptor tyrosine kinase, EphA2, is overexpressed in more than 75% of ovarian cancers and is predictive of poor outcome. Although the specific mechanisms are still being investigated, we hypothesized that tumors with EphA2 overexpression will show increased angiogenesis and matrix metalloproteinases (MMPs). Methods: After IRB approval, invasive ovarian tumor samples and clinical data from 77 patients were obtained and analyzed for CD31, EphA2, MMP-9, MMP-2, and MT1-MMP expression. Tumor microvessel density (MVD) was calculated as an average CD31+ vessel count over three hot spots under high-power fields (HPF). Specimens were individually scored by two gynecologic pathologists in a blinded fashion. Results: The mean age of the patients was 59.07 years (range 46-83). EphA2 was overexpressed in 76% of the tumors and was associated with advanced stage (p<0.001) and high grade (p=0.036). MVD was dichotomized to high- (>12 vessels/HPF) and low- (≤12 vessels/HPF) counts; 63% of all tumors had a high MVD. High MVD was significantly associated with advanced stage (80%, p<0.001), presence of ascites (73.6%, p<0.001), and optimal surgical cytoreduction (65%, p=0.02). Vessel density was not associated with tumor grade or histology. MMP expression was scored separately in the stromal (high expression: MMP-2=38%; MMP-9=73.5%; MT1-MMP=38%) and epithelial (high expression: MMP-2=51%; MMP-9=63%; MT1-MMP=44%) compartments. EphA2 was significantly associated with a high MVD (p=0.003) and high expression of stromal MMP-9 (p=0.04), epithelial MMP-2 (p=0.029) and epithelial MT1-MMP (p=0.03). The associations of EphA2 with histologic subtype, stromal MMP-2, stromal MT1-MMP, and epithelial MMP-9 were not statistically significant. Conclusions: EphA2 overexpression in ovarian cancer is strongly associated with critical factors in the angiogenesis pathway. EphA2 targeting may offer novel anti-angiogenic therapeutic approaches in ovarian cancer.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]