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Title: The role of extracellular proteases in stromal-epithelial interactions in gastric cancer
Author: Kandola, Sandhir
ISNI:       0000 0004 5350 793X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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Cancers of the upper gastrointestinal tract present at an advanced stage and carry a poor prognosis. Oesophageal and gastric tumours have a rich stroma composed of vascular cells, immune cells, and myofibroblasts, which promotes tumour growth, invasion and metastasis. In addition, mesenchymal stromal cells (MSCs) are recruited from the bone marrow to the tumour stroma; the mechanisms underpinning this have not yet been defined. Extracellular proteases play a role in cell migration, invasion, and cell signalling and are known to influence cancer growth in conflicting ways. Myofibroblasts present in normal tissue differ from those found in cancer. Cancer-associated myofibroblasts (CAMs) are known to modulate extracellular protease activity by secreting plasminogen activator inhibitor-1 (PAI-1), an inhibitor of the serine protease urokinase plasminogen activator, and matrix metalloproteinases (MMPs). This investigation studies the role of PAI-1 in gastric cancer and assesses the contribution of myofibroblast-derived MMPs to tumour growth. Finally, the role of chemerin in recruiting MSCs has been investigated. The expression of PAI-1 in myofibroblasts was found to be higher than in gastric cancer cells. Overexpression of PAI-1 in gastric cancer cells resulted in decreased cell adhesion and decreased tumour growth in an in vivo subcutaneous xenograft model of gastric tumour growth. The addition of gastric CAMs potentiated the growth of gastric cancer subcutaneous xenografts. This was not accounted for by differences in cell proliferation rate, apoptosis or final stromal content. Xenografts containing CAMs suppress the growth of a contralateral xenograft without CAMs, demonstrating that a long-range signal can be generated as a result of stromal-epithelial interactions. MMP and cathepsin activity was compared between xenografts containing myofibroblasts to those without. MMP activity is increased in xenografts injected with CAMs, compared to those injected with myofibroblasts taken from normal stomach or those with gastric cancer cells alone. In an organotypic co-culture system, MMP inhibition resulted in a decrease in gastric cancer cell invasion. The injection of fluorescently labelled MSCs injected resulted in homing of these cells to subcutaneous oesophageal tumours containing CAMs. Antagonism at the ChemR23 receptor inhibited this MSC homing to oesophageal xenografts containing CAMs. This work emphasises the importance of assessing the contribution of specific proteases and their inhibitors in gastric cancer. The stroma is an important contributor to extracellular protease activity and myofibroblasts contribute both proteases and their inhibitors to the tumour microenvironment, resulting in the modulation of tumour growth and cell adhesion. MSCs are recruited to oesophageal tumours via a novel signalling pathway.
Supervisor: Varro, Andrea; Dockray, Graham Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)