Functional Identification of Cripto-1 (TDGF1) Role in Glioblastoma Multiforme
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Glioblastoma multiforme (GBM) is one of the most aggressive tumours and has poor survival rate. The expression of the embryonic stem cell factor Crypto-1 has been documented in most cancer types. More specifically, Cripto-1 expression has recently been correlated with low survival rate of young glioblastoma patients. It has been demonstrated that Cripto-1 controls cell survival and stemness, as well as proliferation and epithelial to mesenchymal transition (EMT). The contribution of Cripto-1 to tumour vascularisation was also reported. Even though Cripto-1 expression and signalling in most cancers has been well characterised, its involvement in controlling glioblastoma cells is poorly studied. The aim of this thesis was to interrogate the contribution of Cripto-1 to multiple processes mediating gliomagenesis and further to understand the underlying signalling pathways impacted upon by Cripto-1. The findings of the current study are in line with those reported for other tumour models. Moreover, this study provides further evidence on the important roles Cripto-1 plays in tumourigenesis, particularly, its role in de-differentiating cancer cells. This was shown by confirming its effect on the activation of factors known to maintain cancer cells in an undifferentiated state like OCT4, NANOG and SOX2. Most significantly, this study has unravelled for the first time the positive effect of ectopic Cripto-1 expression on CD44, a cell surface marker known for its involvement in maintaining GBM stem like cells in their undifferentiated phenotype. We also show that Cripto-1 is indispensable in controlling the infiltrative phenotype of glioma cells via regulating EMT. Ectopic Cripto-1 expression also regulates the proliferation of this GBM cell model by increasing levels of the proliferation markers Ki-67 and cyclin D1. This led to a significant increase in cellular growth rate over time. These findings suggest that Cripto-1 might control cellular proliferation in GBM.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
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In order to comply with copyright the following figures have not been published here: Figures 1.1, 1.2, 1.3, 1.4, 1.5, 4.2, 4.3, 4.4.
Glioblastoma multiforme (GBM)