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The response of tumour-infiltrating myeloid cells to the chemotherapy-treatment of tumours

Harwood, Reuben (2013) The response of tumour-infiltrating myeloid cells to the chemotherapy-treatment of tumours. PhD thesis, University of Sheffield.

Corrected Thesis - Reuben Harwood for Submission.pdf
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Myeloid cells are a major component of most forms of malignant tumour. The plasticity of such cells means that they can alter their phenotype in response to changes in the tumour microenvironment, including the pronounced ones that take place after chemotherapy. Tumour cell death, as well as the various cytokines and chemokines released by cells in tumours after such treatments, are now known to alter both the recruitment and function of myeloid cells. Recent studies have shown that monocytes recruited into tumours during/following chemotherapy can promote tumour chemoresistance and metastasis. The data presented in this thesis suggest that, following chemotherapy, tumour-associated macrophages (TAMs) may increase their expression of the neutrophil-recruiting chemokines, CXCL1, CXCL2 and CXCL5, and possibly stimulate the intratumoural accumulation of neutrophils. Responding to these CXC chemokines (and possibly other secreted factors in chemotherapy-treated tumours), neutrophils may then upregulate their expression of such inflammatory cytokines as TNFα, CCL2 and CCL3. Furthermore, data from in vitro invasion assays suggest that neutrophil-derived TNFα is capable of inducing tumour cell invasiveness. Notably, the number of tumour-infiltrating neutrophils was significantly increased after chemotherapy in 3 of the 4 mouse tumour models used. Furthermore, in all 4 tumour models there were significantly more TNFα+ neutrophils after chemotherapy compared to control tumours. Combined treatment with chemotherapy and SB 265610, a CXCR2 antagonist that inhibits CXCL1, CXCL2 and CXCL5 signalling, successfully reduced both the number of these tumour-infiltrating, TNFα+ neutrophils, and the overall level of immunodetectable TNFα in tumours after chemotherapy. Although TNFα is known to be capable of supporting tumour growth, angiogenesis and metastasis, it remains to be seen whether such an increase in neutrophil TNFα expression contributes significantly to the post-chemotherapy regrowth of either primary or metastatic tumours. This could be achieved by giving chemotherapy to mice in which TNFα has been selectively knocked out/down in neutrophils. Data presented here suggest that combining chemotherapy with CXCR2 inhibitors like SB 265610 to inhibit the above neutrophil-mediated events could improve patient tumour responsiveness to chemotherapy and reduce tumour relapse.

Item Type: Thesis (PhD)
Keywords: Tumor; Myeloid; Chemotherapy; Macrophages; Neutrophils
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.617130
Depositing User: Mr Reuben Harwood
Date Deposited: 18 Aug 2014 11:15
Last Modified: 07 Nov 2018 13:35
URI: http://etheses.whiterose.ac.uk/id/eprint/6640

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