Exploring mechanisms of prostate tumourigenesis in mouse models

Doctoral thesis English OPEN
Cox, Adam

Many cell signalling pathways contribute to prostate cancer (PCa) initiation and survival, but the interplay between them remains poorly understood. In this thesis, conditional transgenic models were employed to investigate the impact of mutating the proto-oncogenes β-catenin, and Kras, and the tumour suppressor gene PTEN, alone and in combination within the murine prostate.\ud β-catenin and Pten single mutants display progression from PIN to invasive adenocarcinoma that appears similar to human Gleason pattern 3. Tumours demonstrate co-activation of the Wnt, PI3K/Akt/mTOR, and Ras/MAPK pathways. Kras single mutants develop PIN but do not progress to adenocarcinoma. Double and triple mutants develop more aggressive tumours comparable to Gleason pattern 4. Furthermore, double and triple mutants display upregulated Wnt, PI3K/Akt/mTOR and Ras/MAPK signalling. Expression of p63 negatively correlates with tumour grade, and moreover, progression from PIN to invasive adenocarcinoma is characterised by the synergistic elevation of AR and Ki67, which parallels human PCa.\ud Malignant transformation of a normal prostate epithelial stem cell (PrSC) gives rise to the cancer stem cell (CSC), which may contribute to castrate-resistant PCa. In this study a 3D primary tissue culture assay was optimised to allow maintenance and expansion of prostate cells that display stem-like characteristics in vitro.\ud PrSCs can be isolated by fluorescence activated cell sorting for the antigenic profile Lin-Sca1+CD49f+TropHi, and consistently form spherical structures in Matrigel. PrSCs can withstand multiple round of passage in vitro, and demonstrate the ability to maintain an undifferentiated state. PrSC spheres possess a basal phenotype, supporting a basal location of PrSCs in prostate epithelium.\ud In summary, these mouse models of PCa demonstrate cooperation between important cell signalling pathways in prostate tumourigenesis, and provide a platform for testing novel therapeutics. In addition, the successful isolation and cultivation of cells with stem-like attributes will allow their unique biological properties to be explored further, providing a baseline standard with which to compare the function of CSCs.
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