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Title: Modulation of breast cancer stem cell plasticity and tumourigenesis : evidence for regulatory roles of heparan sulphates
Author: Baty, R. S.
ISNI:       0000 0004 6425 187X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Sub-populations of cancer cells have been identified in tumours, leading to the cancer stem cell (CSC) hypothesis, wherein these sub-populations of cells are crucial in tumour recurrence and chemoresistance. This has given rise to interest in the potential to target these cells for effective new anti-cancer therapies. However, little is yet known about the role of extracellular matrix (ECM) components such as heparan sulphate proteoglycans (HSPGs) in the modulation of CSCs. We hypothesised that targeted modulation of HS in CSCs may lead to altered cell phenotype and reduced metastatic potential. To study HS involvement in CSC homeostasis, an in vitro model of CSCs was established, using flow cytometry to detect and isolate a well described breast cancer stem cell (BCSC) subpopulation with the marker phenotype CD44+ /CD24- in two breast cancer cell (BCC) lines (MDA-MB-231 and Hs578-T). Characterization of these CSCs demonstrated that they possessed typical properties including higher proliferation, invasion, migration, adhesion, and lower apoptosis and drug sensitivity, compared to non-CSCs from the same lines. They also expressed elevated levels of pro-angiogenic factors and stem cell markers. HS, heparin and modified heparins were then added exogenously to these cells in functional assays. This resulted in significant reductions in the proportion of CD44+ /CD24- cells, in a dose responsive and structure-dependent manner. Some of these compounds also reduced the cell proliferation, invasion, migration, adhesion, and chemoresistance of these CSCs, and increased apoptosis, indicating a phenotypc switch towards non-metastatic behaviour. Initial investigation of the mechanisms involved showed altered stem cell and angiogenesis markers including Ang-1, Ang-2, CXCR4 and IL-8. Furthermore, the decrease in the rates of invasion, migration and adhesion strongly correlated with differential inhibition of FGF2/ERK1/2 and IL-6/STAT3 signaling, and other pathways involving AMPKa and mTOR were also implicated in a signaling pathway screen. The key conclusions from these studies are that CD44+ /CD24- cells with CSC properties may be manipulated by targeting their cell surface proteoglycans using HS and heparins with divergent structures. This suggest that HSPGs play an important role in regulating the homeostasis of BCSCs, and further that this class of compounds represent promising novel agents for targetted therapeutic interventions designed to modulate the CSC component in breast cancers.
Supervisor: Turnbull, Jerry Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral