Surgery (RMH) - Theses
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ItemThe role of IL-11 signaling in glioblastoma progression( 2022)Glioblastoma is the most common and lethal brain tumour in adults with a mean survival rate of only 12-15 months with current treatment. The microenvironment of a tumour is becoming increasingly more important to current research, with many findings suggesting that the transcription factors driving oncogenic processes are more often due to cytokine stimulation than gene mutation. There have been multiple signalling molecules and corresponding receptors identified as key role-players in the development of glioblastoma, its severity and ability to evade treatment. Cytokines are molecules that initiate and mediate a range of cellular activities essential to the homeostasis of a heathy person but also to tumour growth, invasion and survival. This includes the critical growth factors and cytokines that activate signalling pathways controlling many pro-oncogenic cellular functions. The interleukin-11 (IL-11) cytokine has become increasingly recognised as a driver of the pathogenesis of a wide range of cancers, however, very little is known regarding its role in glioblastoma. Considering this, we hypothesized that IL-11 would contribute to glioblastoma cell viability, migration, invasion and overall tumour progression. We initially identified that IL-11 and its receptor (IL-11RA) inversely correlate with tumour grade and glioblastoma survival. To study the role of IL-11 in glioblastoma, we next determined the expression of endogenous IL-11RA in a range of cell lines and transfected those expressing very little of the gene with the IL-11RA (cell lines #20 and #28). Proteomic analysis was conducted to reveal changes in protein expression after transfection. A large number of proteins involved in proliferation, migration and invasion were seen to be upregulated in the IL-11RA transfected cells. Indeed, the IL-11RA transfected cells displayed significantly greater growth, migration and invasion in proliferation, wound healing, transwell and spheroid invasion assays. This was reversed with IL-11RA knockdown. The proteomic analysis also highlighted the upregulation of proteins involved in metabolism, particularly glutaminolysis and inhibition of apoptosis. Metabolomic analysis revealed the IL-11RA transfected cells displayed increased levels of glutamine oxidation, as well as increased proliferation and survival of these cells in conditions of depleted glucose or glutamine. Similarly, IL-11RA transfected cells displayed no significant difference in invasion rate in the presence or absence of glucose, when glutamine was available. Alternatively, blocking both glucose and glutamine metabolism with a number of drugs significantly reduced the proliferation, migration and invasion of these cells. Our findings suggest that the IL-11RA transfected cells are able to utilise alternative metabolites such as glutamine, in the absence of glucose, in order to proliferate, migrate and survive. Overall, the results of this thesis suggest that the IL-11RA plays an important role in proliferation, migration, invasion, survival and metabolism in glioblastoma.