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Title: Chemokine regulation of microenvironment-enhanced invasion in prostate cancer
Author: Neisen, Jessica
ISNI:       0000 0004 5369 7200
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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The interaction between a tumour and the surrounding non-malignant stroma impacts on nearly every aspect of malignant progression. The heterogeneity of the tumour microenvironment (TME), however, makes mapping this interaction difficult. Each stromal population contributes to various functions and each tumour type has its own distinct pathway of interaction with different stromal populations. The majority of these interactions are mediated by soluble factors secreted into the TME. The aim of this study was to elucidate the role that IL-8 signalling may play in prostate tumour interaction with the TME and to determine the mechanism by which IL-8 signalling impacts on tumour-associated stromal cells to enhance tumourigenicity. IL-8 in the prostate TME is primarily derived from the tumour cells and bone-marrow derived myeloid cells are capable of responding to tumour-derived IL-8 via high levels of cell surface IL-8 receptors CXCR1 and CXCR2. Direct co-culture of the highly invasive prostate cancer cell line PC3 and a bone marrow-derived, macrophage representative line, THP-1 enhances invasion through Matrigel (2.4-fold, p=0.0098) and increases wound closure after 6 h (50.63% v 25.65% for PC3 cells alone; p=0.010B). Inhibition of IL-8 signalling by neutralizing antibody (i) or PEPducin inhibition of CXCR1 and CXCR2 (ii) inhibited macrophage-dependent invasion and wound closure: (i) 90% decrease in normalized invasion and 43% decrease in wound closure, p<0.001 and p=0.03 respectively relative to IgG and (ii) 38% reduction in wound closure, p=0.0002 compared to non-targeting peptides. Development of a stable PC3-based CXCL810w cell line, PC3-120p, confirmed these findings. PC3-120p cells were unable to initiate THP-1-potentiated motility and invasion, however, this response was rescued by addition of exogenous human CXCLB. Exogenous CXCLB was shown to up-regulate secretion of RTK-activating cytokines and growth factors from THP-1 cells. Addition of the RTK inhibitor cabozantinib (XL 184) but not crizotinib abrogated THP-1-dependent invasion and wound healing response of PC3 cells. Differential analysis of RTKs regulated by both cabozantinib and CXCLB neutralizing antibody in co-culture identify multiple RTKs as potential downstream regulators of CXCLB-dependent, monocyte-enhanced PC3 invasion. Together, this data supports the adjuvant targeting of molecules involved in tumour-stroma interactions to enhance the efficacy of prostate cancer treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available