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

Authors' Affiliations: Departments of ¹ Gynecologic Oncology, ² Quantitative Sciences, ³ Pathology, and ⁴ Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and ⁵ Immunogenetics Section, Department of Transfusion Medicine, NIH, Bethesda, Maryland

Requests for reprints: Ralph S. Freedman, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Unit 1362, Houston, TX 77230. Phone: 713-792-2764; Fax: 713-792-7586; E-mail: rfreedma{at}mdanderson.org.

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 E₂ (PGE₂), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB₄), 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. PGE₂ levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001). Combined levels of PGE₂, 12-HETE, 5-HETE, and LTB₄ 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.