Sinclair, J.R.; (2010) Proteomic analysis of cell models of ovarian cancer tumour suppression. Doctoral thesis , UCL (University College London).

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Abstract

Epithelial ovarian cancer (EOC) is the most common form of gynaecological malignancy in the developed world. Identifying molecular markers of disease may provide novel approaches to screening and could enable targeted treatment and the design of novel therapies. In previous work, 141 primary ovarian tumours were analysed using metaphase comparative genomic hybridization to identify complete or partial chromosome deletions that may harbour tumour and/or metastasis suppressor genes. Chromosome 18 (Ch18) was found to have deletions in 50% of the tumours. Microcell-mediated chromosome transfer (MMCT) of normal Ch18 material into EOC cell lines resulted in hybrids that displayed significant suppression of anchorageindependent growth, invasiveness and reduced tumour growth in nude mice. The major aim of this project was to identify protein changes associated with the tumour suppression observed in the EOC Ch18 MMCT cell models. The project involves a detailed quantitative proteomic comparison of two parental ovarian cancer cell lines (derived from primary endometrioid and clear cell carcinomas) and their MMCT-derived Ch18 hybrid clones. The cellular, secreted and surface proteomes were probed in order to gain comprehensive coverage and to improve the likelihood of useful biomarker identification. A combination of quantitative two-dimensional difference gel electrophoresis (2DDIGE), affinity chromatography and two-dimensional-liquid chromatography and tandem mass spectrometry (2D-LC-MS/MS) have been employed to examine the whole cell, secreted and cell surface proteomes of the parental and hybrid cell models to identify differentially expressed proteins as potential markers of tumour suppression. Proteins of interest have been validated using immune-based detection methods in the parental cell lines, Ch18 hybrids, revertant cell lines, a panel of cancer cell lines and normal ovarian surface epithelium cell lines and in serum from a set of ovarian cancer cases and healthy controls.

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