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Title: Identification of signalling pathways involved in the oxidative stress response triggered by Low Temperature Plasma in prostate epithelial cells and the assessment of tumour-associated allelic expression in prostate cancer
Author: Packer, John
ISNI:       0000 0004 7431 9698
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2018
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Pairing of cancer genome and transcriptome data has revealed that heterozygous mutations aren’t always expressed in cells. The potential for point mutation or genomic rearrangement to alter tumour allelic expression has implications for understanding cellular heterogeneity and application of treatments. Mutation of SPOP, PTEN and IDH-1 was assessed in 51 primary prostate cancer cultures to establish allelic heterozygosity and ascertain whether oncogenic change to coding regions altered allelic expression. No mutations were detected in the three genes, although 18% of tested cultures had loss of heterozygosity in PTEN. The TMPRSS2-ERG fusion, present in half of all prostate cancers, is selectively expressed at an allelic level by cancer stem cells. Monoallelic expression didn’t correlate with TMPRSS2 promoter hypermethylation. Prostate cultures expressed fusion transcript, however epigenetic features of monoallelically expressed genes were not investigated in the epithelial subpopulations. Understanding of allelic chromatin states may inform treatment strategies that permit tumour suppressor expression or oncogenic protein repression. Inability to predict indolent or aggressive progression of organ-confined prostate cancers has created the problem of surgical overtreatment. Focal therapies targeting the tumour core are being met with increasing rates of recurrence, necessitating development of novel treatments. The anti-cancer properties of Low Temperature Plasma (LTP) are being explored in prostate models where it produces autophagy and necrosis through generation of reactive species. Initial gene expression response to LTP and the activation of upstream transcription factors were analysed. LTP activated Nrf2, AP-1 and Notch signalling in patient matched prostate normal and cancer cultures. The progenitor-containing cell fraction was more responsive to LTP than differentiated epithelial cells in both transcription of response genes and nuclear accumulation of active Notch1. When linked to cell-fate outcomes, these immediate molecular responses of prostate cancer to LTP could be used as hallmarks of resistance or treatment efficacy in patients.
Supervisor: Maitland, Norman Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available