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Title: Exploring the impact of doxorubicin on the perivascular niche in cancer
Author: Rowan, Charlotte
ISNI:       0000 0004 6500 3747
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Aims: Previous studies have shown that tumour associated macrophages (TAMs) limit the efficacy of chemotherapy agents like paclitaxel in mouse tumours. Furthermore, perivascular (PV) MRC1+ TAMs stimulate tumour regrowth after their exposure to cyclophosphamide. The aim of this thesis was to investigate the presence and origin of these PV cells in orthotopic mammary (TS1) tumours after doxorubicin (DOX) treatment. Attempts were also made to characterise their interaction with the tumour vasculature in such tumours. Methods and Results: When TS1 tumours had become established in the mammary fat pads of FVB/N mice, their hosts were treated with a single injection of DOX or PBS. 48 hours later, mice were culled and their tumours removed for analysis. Immunofluorescent staining of tumours sections revealed the presence of increased numbers of MRC1+ TAMs in the well-vascularised (normoxic) stromal areas of TS1 tumours, compared to their less well-vascularised, tumour cell islands. Moreover, the number of these cells making direct contact with the tumour vasculature increased after DOX. These cells were mature Gr-1- cells, rather than newly recruited monocytes or immature TAMs. They were not seen to associate with vessels of a particular size. DOX had no effect on the luminal area, patency or pericyte coverage of tumour blood vessels but increased the expression of VegfA mRNA by CD31+ endothelial cells. Moreover, both endothelial cells, and other, as yet undefined cells, upregulated mRNA for Angiopoietin-2, Cx3cl1, Osteopontin and Plgf in response to DOX. Conclusions: DOX increases the number of MRC1+ TAMs associated with blood vessels in TS1 tumours, possibly in response to various genes upregulated by tumour endothelial cells (and other cells in the tumour microenvironment). The impact of these on the recruitment, retention and/or activation of TAMs in the PV niche merits further investigation.
Supervisor: Lewis, Claire ; Staton, Carolyn ; Tozer, Gill Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available