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Eicosanoids and cancer

Key Points

  • The altered metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (LOX) is a common feature of several epithelial-derived malignancies and has been shown to have crucial roles in cancer progression.

  • The production of arachidonic acid-derived prostanoids and leukotrienes occurs in single cells or takes place in a complex manner in which these biologically active lipids, specifically leukotrienes, are generated by transcellular biosynthesis through the cooperation of multiple different types of cells in the tumour and inflamed tissues.

  • Pro-inflammatory prostaglandins and leukotrienes promote tumour growth by regulating tumour epithelial cells themselves and orchestrating the complex interactions between transformed epithelial cells and surrounding stromal cells to establish the tumour microenvironment that facilitates tumour-associated angiogenesis and evades attack by the immune system.

  • Prostaglandins and leukotrienes can modulate tumour epithelial cell proliferation, apoptosis, and migration and invasion through multiple signalling pathways in both an autocrine and paracrine fashion.

  • Prostaglandins and leukotrienes are central molecules in the regulation of stem cell homeostasis.

  • Pro-inflammatory prostaglandins and leukotrienes are key mediators in the crosstalk between tumour epithelial cells and their surrounding stromal cells in establishing a tumour microenvironment with chronic inflammation and immunosuppression.

  • Although non-steroidal anti-inflammatory drugs (NSAIDs), which target COX enzymes, are still among the most promising chemopreventive agents for cancer, cardiovascular and gastrointestinal side effects have dampened enthusiasm for their use as chemopreventive agents. Understanding the roles of prostaglandins and leukotrienes in epithelial-derived tumours and their microenvironment may help to develop cancer biomarkers and chemopreventive and/or therapeutic agents with a greater benefit and fewer side effects than NSAIDs.

Abstract

Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in various pathological processes, such as inflammation and cancer. This Review highlights our understanding of the intricate roles of eicosanoids in epithelial-derived tumours and their microenvironment. The knowledge of how these lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells is crucial for understanding tumour evolution, progression and metastasis. Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents.

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Figure 1: An overview of eicosanoid synthesis pathways.
Figure 2: Models of pro-inflammatory prostaglandins and leukotrienes in promoting cancer progression.
Figure 3: PGE2 and LTB4 promote cancer progression through the induction of tumour epithelial cell proliferation, survival, and migration and invasion.
Figure 4: Prostaglandins and leukotrienes are key pro-inflammatory mediators in orchestrating crosstalk between tumour epithelial cells and immune cells.
Figure 5: PGE2 provides coordinated regulation of tumour immunosuppression.
Figure 6: A model of PGE2 and LTB4 coordinately regulating angiogenesis in the tumour microenvironment.

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Acknowledgements

This work is partly supportedby the US National Institutes of Health Grants RO1DK 62112, P01-CA-77839, R37-DK47297 and P30 DK-58404 (R.N.D.). R.N.D. (R37-DK47297) is recipient of an NIH MERIT award. We also thank the National Colorectal Cancer Research Alliance (NCCRA) for generous support (R.N.D.). We also kindly thank D. Menter for his assistance in the preparation of figures.

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Glossary

Cysteinyl leukotriene (CysLT)

Leukotriene that contains the amino acid cysteine conjugated to the lipid backbone.

ApcMin/+ mice

Carry a point mutation in one Apc allele and spontaneously develop intestinal adenomas. Used as a model for human familial adenomatous polyposis and for human sporadic colorectal cancer.

Azoxymethane (AOM) mouse model

One of the chemically induced colorectal cancer models in which mice are exposed to a chemical carcinogen, AOM.

T helper 17 (TH17) cells

A functional subset of CD4+ T helper cells that secrete particular inflammatory cytokines, including interleukin-17, which mediate pathogenic responses in autoimmune diseases.

Dendritic cells

Bone marrow-derived immune accessory cells that function as antigen-presenting cells for naive T cells and that lead to the initiation of adaptive immune responses to protein antigens.

Cytotoxic T cells

A subgroup of T cells (also known as CD8+ T cells or killer T cells) that are capable of recognizing and inducing the death of infected somatic or tumour cells. CD8+ T cells are recognized as cytotoxic T cells once they become activated.

Regulatory T cells

A T cell subpopulation that suppresses activation of other T cells and maintains immune system homeostasis and peripheral tolerance to self-antigens.

Myeloid-derived suppressor cells (MDSCs)

Immature myeloid cells with potent immunosuppressive functions.

Cross-presentation

A mechanism by which a professional antigen-presenting cell takes up, processes and presents extracellular antigens from a third cell (for example, a virus-infected or tumour cell) with major histocompatibility complex class I molecules to activate a naive CD8+ T cell.

T cell tolerance

Unresponsiveness of the adaptive immune system to antigens, as a result of the inactivation or death of antigen-specific T cells, which is induced by exposure to the antigens.

ApcΔ716 mice

Generated by inserting neomycin into exon 15 of Apc, which results in truncated APC at codon 716. Spontaneously develop intestinal adenomas and are another model for human familial adenomatous polyposis and sporadic colorectal cancer.

Chick chorioallantoic membrane system

A biological assay using the well-vascularized chorioallantoic membrane of the chicken egg to evaluate the biological activity of pro-angiogenic and anti-angiogenic factors.

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Wang, D., DuBois, R. Eicosanoids and cancer. Nat Rev Cancer 10, 181–193 (2010). https://doi.org/10.1038/nrc2809

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