Eicosanoids are bioactive
lipid mediators derived from
arachidonic acid(1) (AA), which is released by cytosolic
phospholipase A2 (cPLA2). AA is metabolized through three major pathways,
cyclooxygenase (COX),
lipoxygenase (LO) and
cytochrome P450, to produce a family of
eicosanoids, which individually have been shown to have pro- or anti-tumorigenic activities in
cancer. However,
cancer progression likely depends on complex changes in multiple
eicosanoids produced by
cancer cells and by tumor microenvironment and a systematic examination of the spectrum of
eicosanoids in
cancer has not been performed. We used liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) to quantitate
eicosanoids produced during lung
tumor progression in an orthotopic immunocompetent mouse model of
lung cancer, in which
Lewis lung carcinoma (LLC) cells are injected into lungs of syngeneic mice. The presence of
tumor increased products of both the
cyclooxygenase and the
lipoxygenase pathways in a time-dependent fashion. Comparing
tumors grown in cPLA2 knockout vs wild-type mice, we demonstrated that
prostaglandins (
PGE2,
PGD2 and PGF2a) were produced by both
cancer cells and the tumor microenvironment (TME), but
leukotriene (
LTB4,
LTC4,
LTD4,
LTE4) production required cPLA2 expression in the TME. Using flow cytometry, we recovered
tumor-associated neutrophils and 2 types of tumor-associated macrophages from
tumor-bearing lungs and we defined their distinct
eicosanoid profiles by LC/MS/MS. The combination of flow cytometry and LC/MS/MS unravels the complexity of
eicosanoid production in
lung cancer and provides a rationale to develop therapeutic strategies that target select cell populations to inhibit specific classes of
eicosanoids.