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Title: Investigating the mechansim of neutrophils recruitment to head and neck cancer in vitro and in vivo
Author: Niaz, Hanan
ISNI:       0000 0004 6060 8026
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Tumour-associated neutrophils (TAN) can have a significant impact on the tumour microenvironment via release of potent growth and angiogenic factors, chemokines and proteinases that can profoundly influence tumour progression. Moreover, several studies have shown that increased neutrophil numbers systematically or within the tumour correlate with an unfavourable prognosis in head and neck squamous cell cancer (HNSCC) patients. The aims of this study were to identify which factors are responsible for neutrophil recruitment into HNSCC and if TAN affect tumour growth in an in vivo model. The number of TAN within human HNSCC tissue was evaluated by immunohistochemical staining for the neutrophil marker myeloperoxidase (MPO). The factors secreted by FaDu HNSCC multi-cellular tumour spheroids (MCTS) were analysed by cytokine array and ELISA. Neutrophils isolated from the peripheral blood of healthy volunteers were used to measure neutrophil migration to factors identified from the array, then the recruitment of neutrophils to MCTS was assessed overtime by flow cytometry in the absence and presence of small molecule inhibitors. FaDu xenograft mouse models were used to confirm the effect of these inhibitors on neutrophil recruitment in vivo and also on tumour growth. MPO staining confirmed the presence of marked numbers of TAN in HNSCC compared to normal oral epithelium. HNSCC MCTS resemble in vivo tumours, displaying areas of hypoxia, necrosis and cell proliferation. Neutrophils migrated to recombinant CXCL8, CXCL1 and MIF and these chemoattractants were found in the conditioned medium of FaDu MCTS. The recruitment of neutrophils into FaDu MCTS was significantly inhibited when neutrophils were pre-treated with antagonists for CXCR2 and CXCR4, the receptors for CXCL8, CXCL1 and MIF respectively. Moreover, use of the MIF inhibitor, ISO-1 caused a dramatic reduction in the number of neutrophils recruited into FaDu MCTS. In addition, in vivo, ISO-1 significantly reduced the number of TAN by up to 80% in xenograft FaDu tumours. Collectively, these data suggest that CXCL8, CXCL1 and MIF in particular are important in the recruitment of TAN into HNSCC.
Supervisor: Murdoch, Craig Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available