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Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice

van der Weyden, L; Speak, AO; Swiatkowska, A; Clare, S; Schejtman, A; Santilli, G; Arends, MJ; (2018) Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice. Journal of Pathology , 246 (3) pp. 300-310. 10.1002/path.5140. Green open access

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Abstract

Metastasis is the leading cause of death in cancer patients, and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate‐limiting step of this process. We used tail‐vein injection of B16‐F10 melanoma cells into mice to mimic the presence of CTCs and to allow for the assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (encoded by Cyba, Cybb, Ncf1, Ncf2, and Ncf4), all showed decreased pulmonary metastatic colonisation. To understand the role of NOX2 in controlling tumour cell survival in the pulmonary microenvironment, we focused on Cyba‐deficient (Cybatm1a) mice, which showed the most significant decrease in metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cybatm1a mice, owing to the presence of large granulomas composed of galectin‐3 (Mac‐2)‐positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in Cybatm1a mice that were not injected with melanoma cells, and these contributed to their decreased survival. The decreased pulmonary metastatic colonisation of Cybatm1a mice was not due to any overt defects in vascular permeability, and bone marrow chimaeras confirmed a role for the haematological system in the reduced metastatic colonisation phenotype. Examination of the lymphocyte populations, which are known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and natural killer cells in the lungs of Cybatm1a mice, relative to controls. The reduced metastatic colonisation, presence of granulomas and altered immune cell populations observed in Cybatm1a lungs were mirrored in Ncf2‐deficient (Ncf2tm1a) mice. Thus, we show that NOX2 deficiency results in both granulomas and the accumulation of antitumoural immune cells in the lungs that probably mediate the decreased pulmonary metastatic colonisation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Type: Article
Title: Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/path.5140
Publisher version: https://doi.org/10.1002/path.5140
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: metastasis, colonisation, reactive oxygen species, NOX2 granuloma, p22phox
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10061057
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