Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Alison Allan

2nd Supervisor

Dr. Tracy Sexton

Joint Supervisor

Abstract

Prostate cancer (PCa) remains a leading cause of death in men, primarily due to ineffective treatment in the metastatic setting. During this phase of PCa, circulating tumor cells (CTCs) are shed into the bloodstream and their presence and number are important in patient prognosis. The CellSearch® system (CSS) is the only U.S. Food and Drug Administration (FDA) and Health Canada approved instrument for detection of CTCs, making it the current clinical gold standard in CTC technology. Although the CSS provides a minimally invasive means of patient monitoring in the metastatic setting, little is known about the role of CTCs in early-stage PCa. Additionally, examination of the utility of CTC molecular characterization in personalized patient care is an area of great interest. However, the underlying biology of CTCs remains poorly understood. In the present study, we demonstrated that CTCs are detectable in early-stage, post-surgical PCa patients undergoing adjuvant and salvage radiotherapy, and that in combination with other clinicopathological risk factors, CTCs may be useful in predicting treatment failure earlier then currently utilized clinical techniques. Additionally, we provide 2 technical resources outlining the FDA and Health Canada approved process of CTC identification and enumeration using the CSS, the detailed experimental process of user-defined protein molecular characterization using the CSS, and a comparable CTC assay for use in in vivo pre-clinical mouse models of metastasis. Finally, a comprehensive biological examination of the role of the epithelial-to-mesenchymal transition (EMT) in CTC kinetics and metastatic dissemination in PCa is presented, demonstrating that highly mesenchymal PCa cells shed CTCs earlier and in greater numbers during the metastatic cascade and have a greater metastatic capacity then PCa cells with an epithelial phenotype. Collectively these data improve our understanding biology of CTCs in PCa, including CTC kinetics, their relationship with EMT, and metastasis. These results will iii guide future research and technology development in the identification and capture of CTCs with the greatest metastatic potential, and may ultimately lead to changes in patient treatment guidelines.


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