Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

Moore, Gillian; Pidgeon, Graham P.

doi:10.3390/ijms18020236

Cited by 90 publications

(71 citation statements)

References 191 publications

(262 reference statements)

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“…The results of this study are also supported by those of previous preclinical studies demonstrating that leukotriene inhibitors, a therapeutic category that includes the asthma medications montelukast (Singulair ® ), zafirlukast (Accolate ® ), zileuton (Zyflo ® ) and ubenimex (bestatin), inhibit tumors of the lung, esophagus and colon (26)(27)(28)(29). Finally, to the best of our knowledge, the only known human study to examine the effects of leukotriene inhibiting asthma medication found an overall reduced risk of cancer, in general, as well as of breast cancer, in particular; however, this study was limited to asthmatic patients (8).…”

Section: Discussionsupporting

confidence: 85%

Chemoprevention of breast cancer by cyclooxygenase and lipoxygenase inhibitors

2020

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Numerous epidemiological and laboratory investigations have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) exert chemopreventive effects against breast cancer due to their activity against cyclooxygenase (COX), the enzyme that responds to tissue damage by producing inflammatory prostaglandins. Recent laboratory and animal investigations have suggested that a second group of anti-inflammatory compounds, those that inhibit lipoxygenase (LOX)-catalyzed products of the leukotriene cascade, may also have potential for breast cancer chemoprevention and therapy. Therefore, in this study, a case-control investigation was conducted to examine the independent and combined effects of COX and LOX inhibitors in the prevention of breast cancer. A total of 611 incident breast cancer patients were identified and they were compared to 615 cancer-free controls, group-matched to the cases on age, race and county of residence. Data on the past and current use of medications and breast cancer risk factors were ascertained using medical records and a risk factor questionnaire. The results revealed risk reductions for COX (OR, 0.38; 95% CI, 0.27-0.54) and LOX inhibitors (OR, 0.52; 95% CI, 0l.32-0.82). Notably, their combined use produced the greatest risk reduction (OR, 0.26; 95% CI= 0.11-0.65). On the whole, the findings of this study suggest that combinations of compounds with independent effects against COX and LOX have a stronger potential to prevent breast cancer than do the individual compounds.

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Section: Discussionsupporting

confidence: 85%

Chemoprevention of breast cancer by cyclooxygenase and lipoxygenase inhibitors

2020

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“…BLT1 is a specific and high-affinity receptor for LTB 4 , whereas BLT2 exhibits a low affinity for LTB 4 and can bind other eicosanoids. Accumulating evidence indicates that most cancer cells express both BLT1 and BLT2 (44). However, the roles of each LTB 4 receptor in cancer development and progression remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4

Nosaka

Baba

Tanabe

et al. 2018

The Journal of Immunology

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Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB, augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB.

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“…This study also showed that ALOX5 protein expression was associated with high-grade ECs and other adverse prognostic features including nodal metastasis. Indeed, while tumour ALOX5 expression promotes proliferation and survival [61][62][63][64], additional roles in stimulating angiogenesis [65], maintaining stemness [66], and promoting metastasis via immune effector cell interactions have also been reported [22,67,68]. In this study, ECs with high ALOX5 protein expression in combination with low HPGD were associated with a poorer prognosis than tumours with either feature alone.…”

Section: Discussionmentioning

confidence: 63%

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

Cummings

Massey

Mappa

et al. 2018

The Journal of Pathology

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Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography-tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE /PGF inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

Cited by 90 publications

References 191 publications

Chemoprevention of breast cancer by cyclooxygenase and lipoxygenase inhibitors

Chemoprevention of breast cancer by cyclooxygenase and lipoxygenase inhibitors

Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

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