Eicosanoids and cancer

Abstract

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.