Examination of Prostate Cancer Stem-like Cell Associated Factors for their Contribution Towards the Development of Castration Resistant Prostate Cancer
| Autor: | Wong, Nicholas |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Druh dokumentu: | Diplomová práce |
| Popis: | Although early detection and treatment of prostate cancer (PC) shows some benefit, advanced PCs that progress despite androgen deprivation become castration resistant (CRPC). This stage becomes largely incurable as CRPCs are intimately associated with metastasis, the predominant cause of PC-related fatalities. Increasing evidence reveals the role of prostate cancer stem cells (PCSCs) in mediating PC progression. Taking advantage of our putative PCSC population derived from DU145 cells, we have examined a number of candidates for their contribution to PCSC-related PC progression and CRPC development. PKM2 plays a major role in cancer cell metabolism by inducing a shift towards aerobic glycolysis (the Warburg effect) to convert metabolic intermediates into cellular building blocks. PKM2 has also been demonstrated in non-metabolic oncogenic functions. Here we reveal an association with higher Gleason PC tissues, and distinct post-translational modifications in our PCSCs. MUC1 is a well-known tumour associated antigen with widespread oncogenic effect. We demonstrate increased MUC1 expression in our PCSCs, upregulation following docetaxel treatment in vivo, and a unique MUC1 network gene signature which may be used to predict CRPC. FAM84B is a novel protein in cancer, and we demonstrate higher expression of FAM84B in our PCSCs and in two animal models of CRPC. Using gene expression databases, both MUC1 and FAM84B were revealed to associate with metastasis and CRPC. Lastly, CSCs arewidely regarded as being chemoresistant, and we have revealed elevated expression of a drug transporter ABCC2 in our PCSCs and in higher Gleason PC tissues. We also present preliminary evidence that ABCC2 may contribute to docetaxel resistance in DU145 sphere-derived subcutaneous xenografts. Co-expression of these four factors in our putative DU145 PCSCs and their widespread impact on diverse mechanisms of cell proliferation and survival underscores the importance of PCSCs in promoting advanced prostate cancer. Thesis Doctor of Philosophy (PhD) |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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