Clinical Relevance of Increased Endothelial and Mesothelial Expression of Proangiogenic Proteases and VEGFA in the Omentum of Patients with Metastatic Ovarian High-Grade Serous Carcinoma

Boleslaw K Winiarski; Nichola Cope; Mary Alexander; Luke C Pilling; Sophie Warren; Nigel Acheson; Nicholas J Gutowski; Jacqueline L Whatmore

doi:10.1016/j.tranon.2014.02.013

Clinical Relevance of Increased Endothelial and Mesothelial Expression of Proangiogenic Proteases and VEGFA in the Omentum of Patients with Metastatic Ovarian High-Grade Serous Carcinoma

Transl Oncol. 2014 Apr;7(2):267-276.e4. doi: 10.1016/j.tranon.2014.02.013. Epub 2014 Mar 4.

Authors

Boleslaw K Winiarski¹, Nichola Cope², Mary Alexander³, Luke C Pilling¹, Sophie Warren², Nigel Acheson⁴, Nicholas J Gutowski⁴, Jacqueline L Whatmore⁵

Affiliations

¹ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
² Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
³ Northern Devon Healthcare NHS Trust, Barnstaple, UK.
⁴ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
⁵ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. Electronic address: [email protected].

Abstract

Epithelial ovarian cancer (EOC) metastasis to the omentum requires implantation and angiogenesis. We propose that prometastatic changes in the omental endothelium (for angiogenesis) and mesothelium (for implantation) are critical. We investigated the expression of angiogenic proteases [cathepsin D (CD), cathepsin L (CL), and matrix metalloproteinase 2 (MMP2) and MMP9] and vascular endothelial growth factor A (VEGFA) in the mesothelium and endothelium of omentum from patients with EOC with omental metastases and control patients with benign ovarian tumors. Endothelial expression of CL, VEGFA, and MMP9 and mesothelial expression of VEGFA, MMP9, and CD were significantly increased in patients with metastasized EOC. High expression of MMP9 and VEGFA in endothelium and mesothelium and CD in mesothelium was positively associated with poor disease-specific survival (DSS). High MMP9 expression in either endothelium or mesothelium and presence of ascites prospectively showed the greatest risk of shorter DSS [hazard ratio (HR)= 6.16, 95% confidence interval (CI) = 1.76-21.6, P = .0045; HR = 11.42, 95% CI = 2.59-50.35, P = .0013; and HR = 6.35, 95% CI = 2.01-20.1, P = .002, respectively]. High endothelial MMP9 expression and ascites were independent predictors of reduced DSS and overall survival, together resulting in worst patient prognosis. Our data show that omental metastasis of EOC is associated with increased proangiogenic protein expression in the omental endothelium and mesothelium.