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Page 16 of 24 Saier et al. J Cancer Metastasis Treat 2021;7:43 https://dx.doi.org/10.20517/2394-4722.2021.87

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[176]
BLT1 mice due to deficiency in T cell infiltrations . This might contribute to the escape of cancer
patients to checkpoint inhibitor therapies. Although pharmacological leukotriene inhibitors have
demonstrated promising cytotoxic and anti-proliferative effects on cancer cell lines and in animal
[162]
models , few clinical trials have been conducted. LY293111, a well-tolerated inhibitor of BLT1, showed no
significant difference in short-term survival in patients with pancreatic cancer and non-small cell lung
cancer [177,178] . Conversely, cysteinyl leukotriene receptor antagonists (LTRAs), such as montelukast and
zafirlukast, which are widely prescribed anti-asthmatic drugs, show more promising chemopreventive
effects. A large epidemiological study on asthmatic patients showed that LTRA treatments decreased the
risk of cancer development, especially lung, breast, colorectal, and liver cancers . CYSLT antagonists also
[179]
1
confer promising chemopreventive effects in preclinical models [180-184] .

Although the role of 5-LOX metabolites in carcinogenesis is well established both in vitro and in murine
models, few studies have focused on tumor progression and metastasis. MK591, a 5-LOX inhibitor, inhibits
[99]
in vitro invasion of C4-2B human prostate cancer cells . Increased resorption in bone explants induced by
the breast-cancer cell lines MDA-MB-231 and MCF-7 was inhibited by blocking prostaglandin and
leukotriene synthesis . These findings suggest that prostaglandins, as well as leukotrienes, may drive
[185]
osteolytic bone lesions. Unexpectedly, 5-LOX deletion in an immunocompetent orthotopic model of lung
cancer resulted in increased primary tumor growth and metastasis, suggesting an antitumorigenic role for
[186]
some 5-LOX products . Given the crosstalk between the different prostanoid pathways and their possible
opposing effects, caution should be taken in targeting these pathways in cancer.

CONCLUSIONS
[187]
Inflammation plays a prominent role in carcinogenesis and metastasis . Multiples reports have
demonstrated during the past decade that inflammation can promote tumor initiation, cancer cell growth,
and metastasis. Remarkably, chemotherapy, radiation therapy, and surgery frequently result in the
production of pro-inflammatory and pro-angiogenic factors that significantly reduce or even counteract the
efficacy of those anti-cancer therapies [188-195] . Increased knowledge of the tumor microenvironment
composition has brought the concept of tumors as inflammatory sites that do not heal. Beyond their direct
action on both cancer cells and bone cells, LPA, S1P, and eicosanoids also promote inflammation at the
bone metastatic site by inducing the production of pro-inflammatory cytokines and the recruitment of
immune cells. Therefore, therapeutic strategies combining anti-inflammatory drugs and blockers of
bioactive lipids deserve future investigations. However, the recent success of immunotherapies against
various types of cancers has shifted the paradigm that mobilizing the immune system is beneficial against
cancer. Meanwhile, loss of resolution of inflammation has recently emerged as a new mechanism of cancer
pathogenesis [196-202] . This suggests that resolution of inflammation rather than blocking it might be a better
therapeutic approach [203,204] . Resolution of inflammation relates to the clearance of cellular debris by
macrophages resulting in reduced localized pro-inflammatory cytokines . Many specialized pro-resolving
[205]
mediators (SPMs) have been characterized based on their endogenous inhibitory action of inflammation
[205]
such as resolvins, lipoxins, protectins, and maresins . Failure of resolution vs. inflammation in
[206]
carcinogenesis has been reviewed in detail . Interestingly, lipoxin A4 (LXA4), which is also a bioactive
lipid derived from AA following combined activities of 5-LOX and 12-LOX , inhibited osteoclast
[207]
[208]
differentiation and resorption activity . As expected, in vivo, LXA4 treatment prevented ovariectomy-
induced bone loss in mice. Interestingly, serum levels of pro-osteoclastic cytokines (TNF-α, IL-1β, IL-6, and
RANKL) were significantly reduced in ovariectomized animals treated with LXA4. These results support the
hypothesis for direct inhibition of osteoclasts in vivo by LXA4. They also reveal an additional indirect
osteoclastic action of LXA4 via reducing the production of pro-osteoclastic mediators. Therefore, LXA4
appears as a potential new tool for the treatment of osteoporosis as well as bone metastasis. Although the