Cyclooxygenases and lipoxygenases in cancer

Abstract

Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell-cell interactions, cell-matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.

Fig. 1

Arachidonic- and linoleic-derived products. a Schematic representation of the major arachidonic acid-metabolizing enzymes and their products. Only the contribution of COX- and LOX-derived products is discussed in this review. b Linoleic acid can be metabolized by 15-LOX-1, thus producing 13-HODE. c In addition to the generation of 5-HETE (a), 5-LOX-derived 5-HPETE can be metabolized by 5-LOX to form LTA₄. d Consecutive oxygenation of arachidonic acid by 15-LOX and 5-LOX generates lipoxins

Fig. 2

COX-derived eicosanoids in tumorigenesis. Schematic representation of the pro- and anti-angiogenic actions mediated by themajor COX products. These lipids can both promote and/or inhibit tumor growth by acting on tumor cells or the host microenvironment

Fig. 3

LOX-derived eicosanoids in tumorigenesis. Schematic representation of the pro- and anti-angiogenic actions mediated by the major LOX products. These lipids can both promote and/or inhibit tumor growth by acting on tumor cells or the host microenvironment

Fig. 4

LOX–COX-derived eicosanoids in tumorigenesis. a Schematic representation of the generation of cyclic hemiketal (HK) eicosanoids from a converging 5-LOX/COX-2 pathway. Only the generation of HKD₂ is illustrated. b Biosynthesis of hemiketals by a tight interaction between neutrophils– macrophages or neutrophils– tumor cells in an inflamed tumor could play a pro-tumorigenic role by stimulating angiogenesis