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Virchows Arch (2012) 461:3339 DOI 10.1007/s00428-012-1252-9
ORIGINAL ARTICLE
Co-expression of VEGF and CA9 in ovarian high-grade serous carcinoma and relationship to survival
Emma Williams & Stewart Martin & Robert Moss &
Lindy Durrant & Suha Deen
Received: 2 March 2012 /Revised: 4 May 2012 /Accepted: 11 May 2012 /Published online: 15 June 2012 # Springer-Verlag 2012
Abstract Poor prognosis in ovarian high-grade serous carcinoma (HGSC) is largely related to resistance to chemo-therapy. Tumour hypoxia is known to be associated with chemotherapy resistance. Stabilisation of hypoxia-inducible factor-1 upregulates the expression of downstream genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF). This study was undertaken to analyse the hypoxia profile as indicated by the co-expression of VEGF and CA9 and its correlation with survival. VEGF and CA9 expressions were examined in tissue microarray of 97 cases of ovarian high-grade serous carcinoma using immunohistochemistry. High expression of either VEGF or CA9, individually, was associated with decreased overall survival (p00.006 and p00.05 respectively). Combined high expression of both markers, to give a hypoxia profile, was associated with chemotherapy resistance (p00.036) and showed worse overall survival with a significant p value (p00.001). Using multivariate analysis, hypoxia profile was an independent prognostic factor for overall survival (p00.028). The combined high expression CA9 and VEGF phenotype, described as high hypoxia profile group, was significantly associated with increased resistance to chemotherapy and poor overall survival. This group may benefit from combined targeted therapy for effective response in ovarian HGSC.
Keywords Ovarian cancer . Serous carcinoma . Carbonic anhydrase . VEGF
Introduction
Ovarian high-grade serous carcinomas (HGSC) are the most common type of ovarian epithelial carcinomas and have the worst prognosis [1]. The 5-year survival rate is only 30 %, mainly due to chemotherapy resistance [2]. Tumour cells that manage to survive within a cluster of over 1 mm3 undergo a state of hypoxia that necessitates activation of alternative survival pathways. One of the significant alternative pathways is a bypass of the mitochondrial oxidative phosphorylation, using glycolysis instead. On the other hand, the growth of solid tumours depends, at least partly, on establishing new blood supply to facilitate oxygen delivery through the process of angiogenesis; the latter involving production of vascular endothelial growth factor (VEGF), a potent angiogenic factor...