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Title: The chemokine receptor CXCR4 and the malignant transformation of the ovarian surface epithelium
Author: Archibald, Kyra Mhairi
ISNI:       0000 0004 2693 5138
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2010
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Ovarian cancer is the most lethal gynaecological cancer in the Western world today. Mortality remains high, partly due to poor understanding of the pre-malignant changes that occur in ovarian cancers. This thesis describes the characterisation of cells derived from the ovarian surface epithelium that may represent an in vitro model of early malignancy. Cells derived from one of three hTERT immortalised human non-malignant ovarian surface epithelial (IOSE) cell lines with functional Rb and p53 acquired the ability to form colonies in soft agar. These transformed cells (TOSE) had increased senescence and nuclear p53 when compared with the parental IOSE25 cells. While they did not form tumours in nude mice, they fulfilled other hallmarks of transformation, such as loss of anchorage dependence, alterations in cell morphology, loss of contact inhibition and cytogenetic abnormalities. Cytogenetic changes were analysed using high-resolution SNP6.0 arrays, which showed a concise amplification of the chemokine receptor CXCR4 gene locus. CXCR4 is implicated in metastasis and higher levels are found in malignant and pre-malignant lesions than in normal cells. This genomic amplification was accompanied by increased functional CXCR4 protein as assessed by cell motility assays. TOSE cells also exhibited altered signalling downstream of CXCR4 when compared with parental IOSE25 cells. Abrogation of the CXCR4 receptor in TOSE cells reduced the number and the size of soft agar colonies and also reduced senescence, suggesting that CXCR4 is oncogenic. In parallel to amplified CXCR4, TOSE cells also contained epigentically silenced CXCL12, the ligand for CXCR4. This thesis argues that TOSE cells represent pre-malignant ovarian cancer and support an emerging model where pre-malignant cells disseminate down a chemokine gradient to sites of distant metastasis at organs expressing high levels of CXCL12. No CXCR4 amplification was observed in human ovarian cancer. However, hypermethylation of the CXCL12 gene promoter was observed in the ovarian cancer cell line SKOV3 and in three out of four borderline ovarian tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine