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.
Highlights
The microenvironment of a developing tumour is composed of a dynamic variety of non-cancerous immune and stromal cells within a scaffold of extracellular matrix that a tumour depends upon for sustained growth, invasion and metastasis
It is hypothesised that targeting the tumour microenvironment (TME) should lead to reduced risk of drug resistance and tumour recurrence that is often seen with conventional cancer cell targeted treatments [3]
We propose that manipulating LO-dependent AA metabolism in the TME could offer new strategies to block cancer-related inflammation and immune escape
Summary
The microenvironment of a developing tumour is composed of a dynamic variety of non-cancerous immune and stromal cells within a scaffold of extracellular matrix that a tumour depends upon for sustained growth, invasion and metastasis. It has recently been demonstrated that immune stromal expression of 5-LO and other distal enzymes involved in the synthesis of 5-LO-derived leukotrienes were increased in human oesophageal adenocarcinoma compared to normal oesophagus, suggesting a role of the 5-LO signalling in the TME during tumour development and progression [34]. Given that both cancer cells and non-cancer stromal cells are potent producers of eicosanoids, tumour progression will likely involve an integrated response to eicosanoid signalling pathways. There is far less known about BLT2 in immunoregulation compared to BLT1, there is increasing evidence to suggest a prominent role of these receptors in a number of different aspects of cancer development, such as proliferation, survival, angiogenesis and Ras-induced transformation and metastasis, further indicating the relevance of 5-LO metabolites and accompanying receptors as molecular therapeutic targets [67,68,69,70]
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