Understanding modulations of lipid mediators in cancer using a murine model of carcinomatous peritonitis

BACKGROUND: Numerous studies have investigated the possible involvement of eicosanoids, lysophospholipids, and sphingolipids in cancer. We considered that comprehensive measurement of these lipid mediators might provide a better understanding of their involvement in the pathogenesis of cancer. In the present study, we attempted to elucidate the modulations of sphingolipids, lysophospholipids, diacyl‐phospholipids, eicosanoids, and related mediators in cancer by measuring their levels simultaneously by a liquid chromatography‐mass spectrometry method in a mouse model of carcinomatous peritonitis. METHODS: We investigated the modulations of these lipids in both ascitic fluid and plasma specimens obtained from Balb/c mice injected intraperitoneally with Colon‐26 cells, as well as the modulations of the lipid contents in the cancer cells obtained from the tumor xenografts. RESULTS: The results were as follows: the levels of sphingosine 1‐phosphate were increased, while those of lysophosphatidic acid (LysoPA), especially unsaturated long‐chain LysoPA, tended to be increased, in the ascitic fluid. Our findings suggested that ceramides, sphingomyelin, and phosphatidylcholine, their precursors, were supplied by both de novo synthesis and from elsewhere in the body. The levels of lysophosphatidylserine (LysoPS), lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidylethanolamine were also increased in the ascitic fluid, while those of phosphatidylserine (PS), a precursor of LysoPS, were markedly decreased. The levels of arachidonic acid derivatives, especially PGE2‐related metabolites, were increased, while the plasma levels of eicosanoids and related mediators were decreased. Comprehensive statistical analyses mainly identified PS in the ascitic fluid and eicosanoids in the plasma as having highly negative predictive values for cancer. CONCLUSIONS: The results proposed many unknown associations of lipid mediators with cancer, underscoring the need for further studies. In particular, the PS/LysoPS pathway could be a novel therapeutic target, and plasma eicosanoids could be useful biomarkers for cancer.