Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice

Louise van der Weyden, Anneliese O Speak, Agnes Swiatkowska, Simon Clare, Andrea Schejtman, Giorgia Santilli, Mark Arends, David J Adams

Research output: Contribution to journalArticlepeer-review

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 allow for 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 (specifically 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 significantly decreased metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cybatm1a mice due to the presence of large granulomas composed of Galectin3 (Mac2)-positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in undosed Cybatm1a mice, and were responsible for 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 the role of the haematological system in being responsible for the colonisation phenotype. Examination of the lymphocyte populations, known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and NK 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 in the lungs results in both granulomas and an accumulation of anti-tumoural immune cells that likely mediate the decreased pulmonary metastatic colonisation.
Original languageEnglish
JournalThe Journal of Pathology
Early online date30 Jul 2018
DOIs
Publication statusE-pub ahead of print - 30 Jul 2018

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