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Title: The role of macrophages in tumour revascularisation following vascular disrupting treatment
Author: Welford, Abigail Frances
ISNI:       0000 0004 2724 9439
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2010
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The vascular disrupting agent, combretastatin-A-4-phosphate (CA-4-P), induces rapid and selective shutdown of the tumour vasculature and secondary tumour cell death. However, blood flow effects are often reversed within 24 hours of a single dose, accompanied by re-vascularisation and continuation of tumour growth. The main aim of this work was to investigate the role of a subset of tumour-associated macrophages (TAMs) - those expressing the angiopoietin receptor, Tie2 (TEMs) - in these processes. Two murine mammary tumour models were used: the transgenic MMTV-PyMT mouse, which develops mammary tumours at 10-12 weeks and the syngeneic N202 mammary tumour, as subcutaneous implants in immunocompetent FVB mice. Twenty-four hours after 50mg/kg CA-4-P, sections of MMTV-PyMT tumours showed elevated levels of hypoxia (pimonidazole staining), reduced vessel lumen size (CD31 staining) and extravasation of intravenously administered FITC-labelled tomato lectin, indicative of vascular damage. These effects were accompanied by elevated levels of tumour necrosis (haematoxylin and eosin staining) and increased numbers of TAMs and TEMs (immuno-staining and FACS analysis of specific markers). TEMs were found to express higher levels of the highly pro-angiogenic enzyme, matrix metalloproteinase-9 (MMP- 9) and the CXCL12 receptor, CXCR4, than Tie2-TAMs. Inhibition of CXCR4 in MMTV-PyMT mice using the CXCR4 inhibitor, AMD3100, resulted in TEM depletion and increased tumour necrosis after CA-4-P treatment. An influx of TEMs and induction of necrosis were also evident in N202 tumours after CA-4-P treatment. Here, depletion of TEMs, using ganciclovir-activated gene knockout of Tie2+ bone marrowderived cells, resulted in higher levels of CA-4-P-induced tumour necrosis than was seen after CA-4-P alone. Collectively, these data suggest that TEMs are involved in the recovery of tumours after CA-4-P treatment, although the exact role of MMP-9 in this phenomenon warrants further investigation. Targeting TEMs may therefore increase the clinical efficacy ofVDAs such as CA-4-P.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available