Abstract
Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.
Highlights
Low-grade inflammation and dysregulated immune responses are components of the tumor microenvironment (TME), pivotal for tumor growth and response to immunotherapies (Binnewies et al, 2018)
Arachidonic acid is subsequently converted into leukotrienes in a concerted three-step reaction: first, arachidonic acid (AA) is dioxygenated into 5hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid [5(S)HpETE]; second, 5(S)-HpETE is dehydrated to yield the transient epoxide intermediate, LTA4; and lastly, depending on the presence and functional coupling of 5-LO to its downstream enzymes, LTA4 is further converted to leukotriene B4 (LTB4) by LTA4 hydrolase (LTA4H), or LTC4 by LTC4 synthase (LTC4S), which conjugates LTA4 with glutathione (Peters-Golden and Henderson, 2007; Haeggstrom and Funk, 2011; Wan et al, 2017) (Figure 1)
Leukotrienes are typically generated by activated leukocytes; the impact of these mediators depends on the temporal accumulation and composition of immune cells at various stages of cancer
Summary
Low-grade inflammation and dysregulated immune responses are components of the tumor microenvironment (TME), pivotal for tumor growth and response to immunotherapies (Binnewies et al, 2018). While therapies that target the immune system, such as checkpoint inhibition, have significantly improved cancer prognosis, not all cancer patients respond to immunomodulatory treatments. Some who respond initially may develop treatment resistance and autoimmunity (Wei et al, 2018). Leukotrienes are proinflammatory lipid mediators that initiate inflammation and mount adaptive immune responses for host defense (Peters-Golden et al, 2005; Peters-Golden and Henderson, 2007). Recent studies have demonstrated that leukotrienes play crucial roles in shaping the tumor microenvironment. This review summarizes recent efforts in elucidating how leukotrienes modulate tumor pathophysiology and discuss possible means to harness leukotriene signaling pathways in cancer therapeutics
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