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  • In cancer interactions between the transformed cancer

    2021-02-23

    In cancer, interactions between the transformed cancer coelenterazine and other cell types recruited to the tumor are important. Tumor associated macrophages provide cancer cells with a suitable low-grade inflammatory milieu including growth promoting factors. Our results suggest a novel pro-tumorigenic mechanism based on cell interaction: tumor associated macrophaghes provide LTC4 which lung cancer cells and their exosomes convert to LTD4. Via CysLT1 this promotes survival and migration of the cancer cells. This mode of formation of LTD4 may occur also in other pulmonary inflammatory conditions, and for other cancer forms. However, we did not obtain pleural exudates from other inflammatory diseases, and healthy controls are technically and ethically unavailable. In any case, the high presence of exosomes in pleural exudates and their strong eicosanoid-mediated activity on cancer cells strongly suggest their relevance in cancer progression and metastasis. Finally, both animal models and human studies indicate that targeting CysLT1 with the well tolerated drug montelukast, alone or combined with chemotherapeutic agents, has anti-tumor effects. Our results suggest that in lung cancer tissue, a substantial part of the LTD4 formation may proceed via transcellular routes, depending on GGT-1 in cancer cells and their exosomes, leading to increased cancer cell migration and survival. We therefore propose further studies on using montelukast as a treatment to reduce the risk of lung cancer metastasis.
    Disclosure of potential conflict of interest
    Acknowledgments This work was supported by grants from the Swedish Medical Research Council, The Swedish Cancer Foundation, The Cancer Research Foundations of Radiumhemmet, The Stockholm County Council, The Swedish Heart-Lung Foundation, The Centre for Allergy Research, The Cancer and Allergy Foundation and the ChAMP consortium at the Karolinska Institute, the Hesselman Foundation, and the KID grant of the Karolinska Institute.
    Airway remodeling occurs in chronic asthmatic inflammation, and features of this response include myocyte hyperplasia and hypertrophy. An increase of 50% to 230% and 25% to 150% is observed in the area of airway smooth muscle in fatal and nonfatal asthma, respectively. Increased thickness of the airways may have an important amplifying effect in the contractile response of bronchial smooth muscle cells (BSMC) and may be a major mechanism contributing to airway hyperresponsiveness in asthma., A growing body of evidence suggests that cysteinyl-leukotrienes (cysLTs) may induce airway smooth muscle remodeling in animal models, and potentiate the proliferation induced by growth factors. Cytokines are also thought to contribute to chronic inflammation and airway remodeling observed in asthmatic airways, and asthmatic individuals produce more transforming growth factor (TGF)-β1 and IL-13 than normal subjects., TGF-β1 is a potent profibrotic T3-type cytokine, which may induce structural changes within the airways, such as subepithelial fibrosis, thickening of the reticular lamina, and human airway smooth muscle proliferation by increasing the expression of insulin-like growth factor binding protein-3 (IGFBP-3). IL-13, a T2-type cytokine, may have important effects on gene expression in airway cells that contribute to the phenotypic features of asthma. IL-13 can induce the expression of secreted factors in airway smooth muscle cells, such as basic fibroblast growth factor (bFGF); bFGF induces BSMC proliferation, which could contribute to the asthma phenotype through autocrine or paracrine effects on other airway cells. Data suggest that IL-13 causes subepithelial fibrosis by the production and activation of TGF-β1 in lung macrophages. Although there is no unanimity on the matter, there is evidence showing that the expression levels of IFN-γ, a T1-type cytokine, are increased in asthmatic subjects., There is an increased frequency of IFN-γ producing CD4+ and CD8+ T cells in asthmatic individuals compared with normal subjects. Genetic studies have demonstrated that several loci in chromosome 6q24-q25 are linked either to asthma or wheezing. Interestingly, this region contains the gene coding for the IFN-γ receptor ligand–binding chain. In human bronchial airway smooth muscle, IFN-γ can enhance CysLT1R expression and increase the contractile responses to LTD and thus possibly contribute to the airway hyperreactivity observed in asthma.