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Title: The role of cathepsin S in tumourigenesis
Author: Small, Donna
ISNI:       0000 0004 2745 1223
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Recent studies have demonstrated that cysteine cathepsin S, predominantly from tumour- associated macrophages, promotes tumour development and progression. Conversely, previous work examining human colorectal and brain biopsies have shown that the tumour cells themselves are a major source of CatS. In order to clarify the contribution of stromal- derived versus tumour cell-derived CatS in colorectal tumourigenesis, investigations were carried out using the syngeneic MC38 coloadenocarcinoma cell line, which was found to expressed and produced CatS. Loss-of-function CatS experiments performed on the MC38 cells demonstrated a reduction in invasion, lower activity level and reduced proteolysis, signifying a role for CatS in various aspects of tumourigenesis. Investigations in vivo using CatS null mice revealed a role for both tumour cell and stromal-derived CatS in MC38 tumour development and highlighted that CatS derived from either sources partially compensated for each other, and that depletion from both sources was required for the most significant retardation of tumour growth, This noted anti-tumour effect was characterised by a reduction in tumour cell proliferation and increased apoptosis, which may be attributable, at least in part, to the significant diminution in tumour neo-angiogenesis. Mean vessel number and vessel area was significantly reduced in tumours which lacked both sources of CatS, were the vessels presented with increased leakiness; suggestive of more dysfunctional tumour vessel architecture, The observation of increased lung and liver metastases in the CatS null mice was unexpected, however, this may be due to the expression of tumour cell derived CatS, thereby promoting rnetastases. This may be a result of decreased immuno-protective and anti-tumour roles due to the loss of CatS. Taken together, these findings clearly highlight a functional role for CatS in several hallmarks of tumourigenesis, particularly angiogenesis. The data also demonstrates CatS as a valid anti-angiogenic target in the treatment of cancer, at least in solid tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available