There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.

One of the most urgent requirements in prostate cancer diagnosis is the development of a blood-based test which would be able to distinguish prostate cancer from benign prostate hyperplasia (BPH). Previously published results found a significant difference between specific glycan levels in patients with advanced prostate cancer and healthy controls. N-Glycans from the whole serum glycoproteins were measured using our fully quantitative high-throughput N-glycan analysis in combination with exoglycosidase digestions in sera from 13 BPH and 34 prostate cancer samples (17 Gleason score 5 and 17 Gleason score 7). The levels of core-fucosylated biantennary glycans and α2-3-linked sialic acids were significantly increased in prostate cancer patients compared with patients with BPH. Triantennary trigalactosylated glycans and tetraantennary tetrasialylated glycans with outer arm fucose were significantly decreased, and tetraantennary tetrasialylated glycans increased in Gleason 7 compared with Gleason 5. All these glycans can distinguish prostate cancer patients from BPH or Gleason 7 from Gleason 5 prostate cancer patients better than the current clinical test, prostate-specific antigen; therefore, their measurement may provide a new noninvasive approach to diagnose prostate cancer. However, additional validation studies would need to be carried out to further support this finding. Decreases in triantennary trigalactosylated glycans and/or bisected core-fucosylated biantennary monosialylated glycans and increases in tetraantennary tetrasialylated glycans correlate with perineural invasion, which could further help to diagnose tumor spread and predict patients’ survival.

Docetaxel is the main treatment for advanced castration‐resistant prostate cancer; however, resistance eventually occurs. The development of intratumoral drug‐resistant subpopulations possessing a cancer stem cell (CSC) morphology is an emerging mechanism of docetaxel resistance, a process driven by epithelial–mesenchymal transition (EMT). This study characterised EMT in docetaxel‐resistant sublines through increased invasion, MMP‐1 production and ZEB1 and ZEB2 expression. We also present evidence for differential EMT across PC‐3 and DU145 in vitro resistance models as characterised by differential migration, cell colony scattering and susceptibility to the CSC inhibitor salinomycin. siRNA manipulation of ZEB1 and ZEB2 in PC‐3 and DU145 docetaxel‐resistant sublines identified ZEB1, through its transcriptional repression of E‐cadherin, to be a driver of both EMT and docetaxel resistance. The clinical relevance of ZEB1 was also determined through immunohistochemical tissue microarray assessment, revealing significantly increased ZEB1 expression in prostate tumours following docetaxel treatment. This study presents evidence for a role of ZEB1, through its transcriptional repression of E‐cadherin to be a driver of both EMT and docetaxel resistance in docetaxel‐resistant prostate cancer. In addition, this study highlights the heterogeneity of prostate cancer and in turn emphasises the complexity of the clinical management of docetaxel‐resistant prostate cancer.

While progression from normal prostatic epithelium to invasive cancer is driven by molecular alterations, tumor cells and cells in the cancer microenvironment are co-dependent and co-evolve. Few human studies to date have focused on stroma. Here, we performed gene expression profiling of laser capture microdissected normal non-neoplastic prostate epithelial tissue and compared it to non-transformed and neoplastic low-grade and high-grade prostate epithelial tissue from radical prostatectomies, each with its immediately surrounding stroma. Whereas benign epithelium in prostates with and without tumor were similar in gene expression space, stroma away from tumor was significantly different from that in prostates without cancer. A stromal gene signature reflecting bone remodeling and immune-related pathways was upregulated in high compared to low-Gleason grade cases. In validation data, the signature discriminated cases that developed metastasis from those that did not. These data suggest that the microenvironment may influence prostate cancer initiation, maintenance, and metastatic progression.

Increasing levels of tissue hypoxia have been reported as a natural feature of the aging prostate gland and may be a risk factor for the development of prostate cancer. In this study, we have used PwR-1E benign prostate epithelial cells and an equivalently aged hypoxia-adapted PwR-1E sub-line to identify phenotypic and epigenetic consequences of chronic hypoxia in prostate cells. We have identified a significantly altered cellular phenotype in response to chronic hypoxia as characterized by increased receptor-mediated apoptotic resistance, the induction of cellular senescence, increased invasion and the increased secretion of IL-1β, IL6, IL8 and TNFα cytokines. In association with these phenotypic changes and the absence of HIF-1α protein expression, we have demonstrated significant increases in global levels of DNA methylation and H3K9 histone acetylation in these cells, concomitant with the increased expression of DNA methyltransferase DMNT3b and gene-specific changes in DNA methylation at key imprinting loci. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic hypoxic conditions in the prostate. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular phenotype with a potential role in tumour development.