An in vitro and in vivo investigation into tumour initiating cells in human prostate cancer cell lines

A cell type often referred to as a prostate tumour initiating cell is thought to be responsible for the occurrence of androgen-independent and chemo-resistant prostate cancers. Cell surface markers used to identify normal stem cells have been used to isolate prostate tumour initiating cells from human primary tumour samples due to their common characteristics. However, because of the heterogeneity in different tumours, whether these cells truly represent a single cell type remains under debate. The frequent mutations that occur in cancer cell lines complicate the identification of such cells in prostate cancer lines, as does the in vivo microenvironment seen in mouse models. Thus, standard protocols for isolating tumour initiating cells from prostate cancer cell lines have not yet been developed. The role of the putative tumour initiating cell in the development of treatment resistance is also unknown. In this thesis, isolation of putative tumour initiating cells from the PC3 and LNCaP prostate cancer cell lines was attempted. It was demonstrated that PC3 cells with high aldehyde dehydrogenase (ALDH) activity showed tumour-initiating characteristics both in vivo and in vitro. Moreover, high ALDH activity was correlated to highly tumourigenic and aggressive PC3 cells which developed greater chemotherapy resistance and increased angiogenesis. Cells with high ALDH activity may thus be a potential cancer therapeutic target for advanced prostate cancer (chapters 2-4). To broaden the technical aspects of this thesis, chapter 5 expands our work from tumour initiating cells to the field of medicinal chemistry aimed at identifying new cancer therapy drugs (chapter 5). In this chapter the pharmacological action of a series of analogues of noscapine which is a naturally occurring compound extracted from the papaver were examined. Of all 45 noscapine analogues tested, it was demonstrated that analogues containing 7-chloro and N-ethyl urea functionality are the most active in both efficacy and potency indicating that these two noscapine analogues could be a potential new oral-active, low-toxicity anticancer agents. In conclusion, although in this thesis we were not able to fully demonstrate cancer cells with high ALDH activity from prostate cancer cell lines were putative prostate tumour initiating cells, this population of cells showed tumour initiating cell like characteristics, analysis of ALDH activity in clinical prostate cancer samples may become useful for the stratification of prostate cancer patients at greater risk of developing lethal metastatic disease.