Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer

Abstract

Purpose: To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC). Experimental Design: We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E 2 (PGE 2 ), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB 4 ), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachidonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvic disease. Results: (a) Eicosanoid products were detected in tumor, MP, and BP specimens. PGE 2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001).Combined levels of PGE 2 , 12-HETE, 5-HETE, and LTB 4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of MP, BP, and tumor showed that a number of eicosanoid and arachidonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors. Conclusions: Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachidonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC.Eicosanoids is a collective term for oxygenated derivatives of different 20-carbon fatty acids such as leukotrienes and prostanoids (prostaglandins, prostacyclins, and thromboxanes). These bioactive lipids have important functional roles in regulating many physiologic processes and inflammatory responses (1). Eicosanoid production is a tightly regulated process that depends on (a) the acylation and transfer of arachidonic acid into specific phospholipid pools by arachidonic acid -selective acyltransferase and transacylase reactions and (b) the release of these pools by a variety of phospholipase A 2 (PLA 2 ) enzymes (2).Arachidonic acid liberated by PLA 2 is metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes variously expressed in cells and tissues, and contribute to the production of specific metabolites (1, 3, 4). These bioactive lipids or eicosanoids then exert their biol...

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