The mechanism of ovarian cancer chemoresistance
Ovarian cancer (OC) is the leading cause of female reproductive tract cancer mortality in the world. Although cytoreductive surgery followed by platinum/taxane acts a standard therapy and contributes to a high initial response rate, most patients will ultimately develop tumour recurrence and succumb to chemoresistant disease. Therefore, improved targeting therapies and chemosensitisation strategies are essential for reducing the mortality of this devastating malignancy. This thesis investigates roles of epithelial-mesenchymal transition (EMT), cancer stem cells (CSC), as well as the PI3K/Akt/mTOR signalling pathway in OC chemoresistance, and provides a range of potential candidate chemoresistant biomarkers with proteomic technologies. The aims of this study were to: 1) compare the expression differences of EMT, CSC and PI3K/Akt/mTOR pathway related biomarkers between the chemosensitive and the corresponding chemoresistant cell lines, and identify whether they are related to OC chemoresistance; 2) investigate the treatment effect of a dual PI3K/Akt/mTOR pathway inhibitor (BEZ235) on OC chemoresistant cell lines, and explore the potential mechanism involved; 3) identify novel potential OC chemoresistant biomarkers with the application of proteomics technology; 4) study the expression of the selected biomarkers on human OC tissues, which includes EMT, CSC and PI3K/Akt/mTOR pathway related biomarkers, as well as the identified potential chemoresistant biomarkers in proteomics experiment, and correlate the expression levels with clinical statistics. The results indicate that EMT, CSC and PI3K/Akt/mTOR pathway play a critical role in OC chemoresistance, which is further confirmed on human OC tissues. The inhibition of the PI3K/Akt/mTOR pathway eliminates the subpopulation with CSC characteristics, reverses EMT, and increases the chemosensitivity to cisplatin in chemoresistant OC cell lines. In addition, some novel candidate chemoresistant biomarkers were identified by proteomic technologies and further confirmed by validation study. In conclusion, this study revealed the critical role of EMT, CSC and PI3K/Akt/mTOR pathway, and provided a promising targeted therapy strategy with the PI3K/Akt/mTOR pathway inhibitor. In addition, the novel chemoresistant biomarkers identified could also have an import impact on the prognosis and treatment of OC chemoresistance in the future.
EMT, Ovarian cancer, Chemoresistance, CSC, PI3K/Akt/mTOR signaling pathway, Proteomics
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