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Title: The meaning of LIF : the role of Leukaemia Inhibitory Factor in prostate cancer-induced bone disease
Author: Turner, Christina Jane
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Bone metastasis is a frequent complication of advanced prostate carcinoma (PCa) and there is an urgent need to elucidate the mechanisms that drive metastasis to identify novel therapeutics and biomarkers. Leukaemia inhibitory factor (LIF) is an IL-6 family cytokine known to be involved in a wide range of biological functions including haematopoiesis and bone formation. Moreover, it has shown to be overexpressed in a number of tumour types including those, which metastasise to bone, but the role in PCa is unknown. The aim of this project is to elucidate the contribution of LIF in PCa bone metastasis. Using in silico analysis I established that increased LIF was associated with disease free survival and freedom from biochemical recurrence in PCa patients. Furthermore, LIF was significantly decreased in metastatic and specifically bone metastatic PCa patients. In vitro knockdown of LIF in PCa cells significantly increased migration and invasion. In contrast, long-term overexpression of LIF increased apoptosis, decreased cell proliferation and significantly increased sensitivity to chemotherapy. RNA-seq analysis of PCa cells with overexpression of LIF revealed a significant upregulation of the interferon pathway, In silico analysis of murine models of PCa bone disease showed upregulation of LIF in the bone microenvironment, which was supported by in vitro co-cultures systems and accompanied by an upregulation of RANKL and a downregulation of OPG. LIF treatment of bone stromal cells caused an increase in differentiation towards osteoblasts at the expense of adipocytes, with LIF serum levels correlating with late stage weight loss in tumour bearing mice as well as leptin levels. My results indicate that LIF may be a double-edged sword in PCa. LIF is inversely correlated with metastasis in human PCa patients and caused decreased proliferation and increased apoptosis in PCa cells, but with functional effects in cells of the tumour-bone niche that may promote disease progression in advanced PCa.
Supervisor: Edwards, Claire ; Hamdy, Freddie Sponsor: Prostate Cancer UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available