Comparative analysis of peritoneum and tumor eicosanoids and pathways in advanced ovarian cancer.
OBJECTIVE
To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC).


METHODS
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.
Freedman
Ralph S
RS
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230, USA. rfreedma@mdanderson.org
Wang
Ena
E
Voiculescu
Sonia
S
Patenia
Rebecca
R
Bassett
Roland L
RL
Deavers
Michael
M
Marincola
Francesco M
FM
Yang
Peiying
P
Newman
Robert A
RA
D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D016718:Arachidonic Acid / Q000737:chemistry; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D018613:Microscopy, Confocal; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010537:Peritoneum / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D021241:Spectrometry, Mass, Electrospray Ionization; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D015777:Eicosanoids; D008055:Lipids; D011956:Receptors, Cell Surface; D016718:Arachidonic Acid; D015232:Dinoprostone