ABSTRACT
5-lipoxygenase is an enzyme responsible for the synthesis of a range of bioactive lipids signalling molecules known collectively as eicosanoids. 5-lipoxygenase metabolites such as 5-hydroxyeicosatetraenoic acid (5-HETE) and a number of leukotrienes are mostly derived from arachidonic acid and have been shown to be lipid mediators of inflammation in different pathological states including cancer. Upregulated 5-lipoxygenase expression and metabolite production is found in a number of cancer types and has been shown to be associated with increased tumorigenesis. 5-lipoxygenase activity is present in a number of diverse cell types of the immune system and connective tissue. In this review, we discuss potential routes through which cancer cells may utilise the 5-lipoxygenase pathway to interact with the tumour microenvironment during the development and progression of a tumour. Furthermore, immune-derived 5-lipoxygenase signalling can drive both pro- and anti-tumour effects depending on the immune cell subtype and an overview of evidence for these opposing effects is presented.
Subject(s)
Arachidonate 5-Lipoxygenase/metabolism , Cell Communication , Neoplasms/metabolism , Neoplasms/pathology , Signal Transduction , Tumor Microenvironment , Adipose Tissue/immunology , Adipose Tissue/metabolism , Animals , Biosynthetic Pathways/drug effects , Cyclooxygenase 2/metabolism , Fibroblasts/immunology , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Immunomodulation , Leukotrienes/biosynthesis , Lipid Metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasms/immunology , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/metabolism , Tumor Microenvironment/immunology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69(+) and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.
