dc.contributor.author | Phillips, Melissa | |
dc.date.accessioned | 2017-05-23T13:28:10Z | |
dc.date.available | 2017-05-23T13:28:10Z | |
dc.date.issued | 2016-10-07 | |
dc.date.submitted | 2017-05-23T13:06:36.359Z | |
dc.identifier.citation | Phillips, M. 2016. The role of the tumour microenvironment in arginine deprivation in malignant pleural mesothelioma. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/23293 | |
dc.description | PhD | en_US |
dc.description.abstract | Approximately 50% of all malignant pleural mesotheliomas (MPM) are deficient in argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine biosynthesis, and are sensitive to arginine deprivation. This discovery in MPM has been translated into the clinic using the arginine depletor pegylated arginine deiminase (ADI-PEG20), which showed a halving in the risk of disease progression in a randomised phase II study. However, unstudied to date, stromal resistance to ADI-PEG20 may reduce its efficacy. Here, I studied the effect of macrophages, abundant in mesothelioma, on the tumour cytotoxicity of ADI-PEG20.
A distinct pro-inflammatory cytokine gene expression signature involved in macrophage recruitment and activation was identified and validated in ADI-PEG20-treated ASS1 negative MPM cell lines. In vivo induction of pro-inflammatory cytokines was also seen in ADI-PEG20-treated patient plasma. Notably, in vitro co-culture experiments demonstrated a significant increase in ASS1 negative MPM cell viability upon co-culture with macrophages in the presence of ADI-PEG20. This was accompanied by a significant increase in ASS1 expression in co-cultured macrophages, with a corresponding increase in argininosuccinate lyase (ASL) expression in co-cultured tumour cells and a doubling in levels of the arginine precursor, argininosuccinate, in cell supernatant. The addition of argininosuccinate to tumour cell media rescued ASS1 negative MPM cells from ADI-PEG20 cytotoxicity, while the macrophage-mediated resistance to ADI-PEG20 was abrogated following ASL knockdown in MPM cells. Finally, xenograft studies demonstrated a significant reduction in tumour volume in mice treated with ADI-PEG20 in combination with macrophage depletion, compared with ADI-PEG20 alone.
Collectively, the data indicate that as a result of metabolic ‘cross-talk’ between macrophages and ASS1 negative MPM cells, macrophages mediate MPM resistance to ADI-PEG20 via the provision of argininosuccinate. My studies provide a rationale for combining ADI-PEG20 with an inhibitor of macrophage recruitment in the treatment of ASS1-deficient mesothelioma. | en_US |
dc.description.sponsorship | Medical Research Council (MRC), the British Lung Foundation (BLF), and the Mick Knighton Mesothelioma Research Fund (MKMRF). | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.rights | The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author | |
dc.subject | Molecular Oncology | en_US |
dc.subject | malignant pleural mesotheliomas | en_US |
dc.subject | macrophages | en_US |
dc.subject | argininosuccinate lyase | en_US |
dc.title | The role of the tumour microenvironment in arginine deprivation in malignant pleural mesothelioma | en_US |
dc.type | Thesis | en_US |