Arachidonic acid is a polyunsaturated fatty acid that constitutes the phospholipid domain of most cell membranes and is liberated from the cellular membranes by cytoplasmic phospholipase A2 (PLA2). Free arachidonic acid can be metabolized to eicosanoids through three major pathways: the cyclooxygenase (COX), the lipoxygenase (LOX) and the cytochrome P450 monooxygenase pathways. In the COX pathway, the key step is the enzymatic conversion of arachidonic acid to the intermediate prostaglandin G₂ (PGG₂), which is then reduced to an intermediate PGH₂ by the peroxidase activity of COX. PGH₂ is sequentially metabolized to prostanoids, including prostaglandins (PGs) and thromboxanes (TXs) by specific prostaglandin and thromboxane synthases. LOXs convert arachidonic acid into biologically active metabolites such as leukotrienes and hydroxyeicosatetraenoic acids (HETEs); P450 metabolizes arachidonic acid into epoxyeicosatrienoic acids (EETs), HETEs and hydroperoxyeicosatetraenoic acids (HPETEs). In the 5-LOX pathway, arachidonic acid is converted to an intermediary 5-HPETE, which is further metabolized to form the unstable leukotriene A₄ (LTA₄). LTA₄ is subsequently converted to 5-HETE, LTB₄, LTC₄, LTD₄ and LTE₄. Each of the prostaglandins and leukotrienes exerts its biological effects by binding to its cognate G protein-coupled receptor. PGI₂ can transactivate the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), and a PGD₂ dehydration product, 15dPGJ₂, is a natural ligand for PPARγ. The multidrug resistance-associated protein (MRP) gene family is comprised of efflux transporters for both prostaglandins and leukotrienes, and PGT is an influx transporter for prostaglandins. Hydroxyprostaglandin dehydrogenase 15-(NAD) (15-PGDH) mainly metabolizes intracellular PGE₂ and PGF_2α to a stable 13,14-dihydro-15-keto-PGE₂ and 13,14-dihydro-15-keto-PGF_2α. The red boxes indicate the signalling pathways that are discussed in this Review. CysLT, cysteinyl leukotriene; NSAID, non-steroidal anti-inflammatory drug.

Following the initiation of epithelial tumours, the reciprocal interactions between transformed epithelial and stromal cells have a key role in facilitating cancer progression. Pro-inflammatory prostaglandins and leukotrienes produced by tumour epithelial cells and their surrounding stromal cells are key mediators in this crosstalk and can accelerate tumour growth and metastasis through several methods. First, the pro-inflammatory prostaglandins (PGs) and leukotrienes (LTs) can directly induce epithelial tumour cell proliferation, survival, and migration and invasion in autocrine and paracrine manners. These pro-inflammatory lipids also stimulate epithelial cells and their surrounding stromal cells to produce growth factors, pro-inflammatory mediators and angiogenic factors, which switch the microenvironment from normal to tumour supporting. The tumour microenvironment, in turn, recruits immune cells and endothelial cells (tumour-infiltrating cells), which produce more pro-inflammatory mediators including eicosanoids, growth factors and angiogenic factors. These factors accelerate tumour growth and stimulate metastatsis through an autocrine loop by inducing angiogenesis and evading attack by the immune system.

Multiple cellular signalling pathways mediate the effects of prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) on the regulation of epithelial tumour cell proliferation, survival, and migration and invasion. PGE₂ stimulates cell proliferation through multiple cascades in both colorectal cancer (CRC) and non-small-cell lung cancer cells. PGE₂ also induces cell proliferation through a glycogen synthase kinase-3β (GSK3β)–β-catenin (β-cat) pathway in CRC cells or by the upregulation of aromatase in breast cancer cells. PGE₂ inhibition of GSK3β reduces β-catenin phosphorylation and thereby prevents its degradation, leading to accumulation, nuclear translocation and functional activity of β-catenin. PGE₂ promotes CRC cell survival by activating a PI3K–Akt– peroxisome proliferator-activated receptor-δ (PPARδ) cascade in vitro and in vivo. In addition, PGE₂ induces CRC cell migration and invasion through β-arrestin-1–SRC–epidermal growth factor receptor (EGFR)–PI3K–Akt signalling in vitro and in vivo. PGE₂ transactivation of EGFR also depends on the extracellular release of an EGF-like ligand in CRC cell lines and a normal gastric epithelial cell line. PGE₂ also induces cell migration and invasion through an Erk–ETS1–matrix metalloproteinase 2 (MMP2) cascade in pancreatic cancer cell lines or through the upregulation of C-C chemokine receptor 7 (CCR7) in breast cancer cell lines. LTB₄ stimulates cell proliferation and promotes cell survival through a BLT1–Erk pathway in CRC cell lines or through both Mek–Erk and PI3K–Akt pathways in human pancreatic cancer cell lines. P, phosphorylation.

During the initiation of epithelial tumours or chronic inflammation, transformed or normal epithelial cells and tissue-resident immune cells locally secrete pro-inflammatory prostaglandins and leukotrienes such as prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄), which recruit large numbers of immune cells from the circulation into the mucosa and reprogramme the immune cells into pro-inflammatory leukocytes. For example, PGE₂ induces expansion of inflammatory T helper 17 (T_H17) cells by regulating interactions between T cells and dendritic cells and facilitates T_H1 differentiation. PGE₂ shifts the interleukin-12 (IL-12)/IL-23 balance in favour of IL-23 through the induction of IL-23 and inhibition of IL-12 expression in dendritic cells. IL-23 is essential for T_H17 expansion and survival, whereas IL-12 suppresses T_H17 development and function. In recruitment of immune cells, PGE₂ induces infiltration of neutrophils and T_H17 cells and enhances dendritic cell migration whereas PGD₂ inhibits dendritic cell migration. LTB₄ has a major role in attracting neutrophils, T cells, dendritic cells and macrophages from the circulation into inflammatory sites. Collectively, PGE₂ and LTB₄ induce the massive infiltration of immune cells and change their functionality, which in turn results in the establishment of a chronic inflammatory microenvironment.

Pro-inflammatory prostaglandin E² (PGE₂) produced by tumour epithelial cells and/or their surrounding stromal cells induces immunosuppression through several ways, including: downregulating anti-tumour T helper 1 (T_H1) cytokines and upregulating immunosuppressive T_H2 cytokines; inhibiting CD8⁺ T cell proliferation and activity, suppressing the anti-tumour activity of natural killer cells and stimulating the expansion of regulatory T cells (T_Reg cells) and myeloid-derived suppressor cells (MDSCs); and inhibiting CD8⁺ T cell anti-tumour functions by impairing the ability of tumour cells to directly present tumour antigen, inhibiting dendritic cell differentiation and switching the function of dendritic cells from induction of immunity to T cell tolerance. The yellow CD8⁺ T cells have anti-tumour activity and the purple CD8⁺ T cell does not have anti-tumour activity. The purple dendritic cells have the ability to present tumour antigens from tumour cells with major histocompatibility complex (MHC) class I molecules to activate naive CD8⁺ T cells. The orange dendritic cell does not have the ability to activate CD8⁺ T cells (T cell tolerance). IFNγ, interferon-γ; IL, interleukin; TNFα, tumour necrosis factor-α.

Pro-inflammatory prostaglandin E₂ (PGE₂) and/or B₄ LTB₄ promote angiogenesis on at least two levels. First, PGE₂ and/or LTB₄ can directly act on epithelial, endothelial and/or immune cells to induce angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2) and the chemokines CXCL1 and CCL2. In transformed epithelial cells, PGE₂ induces VEGF and CXCL1 secretion through an EP2 or EP4–epidermal growth factor (EGFR)–Erk cascade. In endothelial cells, PGE₂ induces VEGF and FGF2 secretion through a MAPK pathway and LTB₄ also stimulates VEGF expression. Moreover, PGE₂ not only binds to endothelial cells to stimulate cell migration through an αVβ3 integrin–CDC42 and Rac pathway, but also mediates VEGF-and FGF2-induced CXCR4-dependent neovessel assembly in vivo. In immune cells, PGE₂ promotes mast cells to release VEGF and CCL2, and LTB₄ stimulates VEGF expression. Secretion of VEGF and FGF2 from tumour epithelial, endothelial and immune cells promotes endothelial cell proliferation and survival, and the chemokine CXCL1 released from tumour epithelial cells stimulates endothelial cell migration and tube formation in vitro and angiogenesis in vivo. CCL2 can attract endothelial cells to the tumour microenvironment. Interestingly, VEGF and FGF2 induce COX2 and subsequently PGE₂ in endothelial cells, and CCL2 also induces COX2 and PGE₂ in macrophages. Therefore, the effects of PGE₂ on the regulation of VEGF, FGF2 and CCL2 are probably amplified through this positive feedback loop.