Ovarian epithelial cancer:: a role for PGE2-synthesis and signalling in malignant transformation and progression

Background: The involvement of the cyclooxygenases (COX), in particular COX-2, is well documented for many tumours, e. g. colon, breast and prostate cancer, by both experimental and clinical studies. There are epidemiological data from subjects using NSAIDs, and experimental evidence supporting the hypothesis of prostaglandins (PGs) as regulators of tumourigenesis in the ovary. One of the end products of PG-synthesis, PGE(2), regulates several key-processes, which are characteristic for tumour growth, e. g. angiogenesis, proliferation and apoptosisis. The present study investigated the pathway for PGE(2) - synthesis and signalling in ovarian tumourigenesis by analysing specimen from normal ovaries (n = 18), benign (B) (n = 8), borderline type (BL) (n = 6) and malignant tumours (AC) (n = 22). The expression and cell-specific localization of COX-1, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and two of the receptors for PGE(2), EP1 and EP2, were examined by immunoblotting (IB) and immunohistochemistry (IHC). Results: The results are in line with earlier studies demonstrating an increase of COX-2 in AC compared to the normal ovary, B and BL tumours. Increased expressions were also observed for COX-1, mPGES-1 and EP-1 which all were significantly ( p < 0.05) augmented in less differentiated AC ( grades: moderately-, poorly- and undifferentiated). The increase of COX-2 was also correlated to stage (FIGO classification) with significant elevations in stages II and III. EP1 was increased in stage III while no significant alterations were demonstrated for COX-1, mPGES-1 or EP2 for stage. IHC revealed staining of the tumour cells, but also increase of COX-1, COX-2, mPGES-1 and EP1 - 2 in the stromal compartment of AC (grades: moderately-, poorly- and undifferentiated). This observation suggests interactions between tumour cells and stromal cells (fibroblasts, immune cells), e. g. paracrine signalling mediated by growth factors, cytokines and possibly PGs. Conclusion: The increases of COX-1, COX-2, mPGES-1 and EP1-2 in epithelial ovarian cancer, supports the hypothesis that PGE2-synthesis and signalling are of importance for malignant transformation and progression. The observed augmentations of COX-1, COX-2 and mPGES-1 have implications for future therapeutic strategies.