Abstract
Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.
Highlights
Eicosanoids represent a family of lipid signaling molecules which are produced through the release of arachidonic acids from membrane phospholipids, and subsequent production through a series of oxygenases
The goal of this review is to focus on the role of eicosanoids as modulators of the tumor microenvironment and anti-tumor immunity
Prostaglandin H2 (PGH2), which is produced through the metabolism of arachidonic acid (AA) by cyclooxygenase-1 or -2 (COX-1/2) can lead to multiple prostanoid products: prostaglandin E2, prostaglandin D2 (PGD2), prostacyclin (PGI2), prostaglandin F1α (PGF1α) and Thromboxane A2 (TXA2), via expression of downstream synthases: PGE2 synthases, PGD synthases, PGI synthase (PGIS) and thromboxane synthases (Seo and Oh, 2017)
Summary
Eicosanoids represent a family of lipid signaling molecules which are produced through the release of arachidonic acids from membrane phospholipids, and subsequent production through a series of oxygenases. Studies demonstrated that PGE2 could act in an autocrine fashion to promote cell proliferation, migration and invasion (Sheng et al, 1998; YipSchneider et al, 2000; Raz, 2002) This resulted in the development of COX inhibitors, COX-2 inhibitors as potential therapeutic agents in cancer (Jacoby et al, 2000; Csiki et al, 2005; Bertagnolli et al, 2006). The last 5 years has seen this come to fruition with the development of immunotherapy, immune checkpoint inhibitors (Topalian et al, 2012; Topalian et al, 2015) These agents, which target pathways that cancer cells use to block antitumor effects of T cells have shown remarkable efficacy in a variety of malignancies, leading to FDA approval (Callahan and Wolchok, 2013; Gajewski et al, 2013). We will review published studies examining this, and indicate where there are gaps in our knowledge regarding the role of this complex family in controlling immunity
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