Although early detection and treatment of prostate cancer (PC) shows clinical benefit, advanced PCs that progress despite androgen deprivation therapy almost invariably result in castration resistance. This progression is lethal as castration-resistant prostate cancer (CRPC) are intimately associated with metastasis and remains the predominant cause of PC-related fatalities. Increasing evidence reveal a critical role of prostate cancer stem cells (PCSCs) in facilitatin g PC progression and acquisition of androgen independence. Taking advantage of our putative DU145 cell derived-PCSC population, we examined a number of candidate proteins for their contribution to PC progression and CRPC development.
We identified three PCSC-specific proteins, BChE, CNTN1 and PCSK9. Butyrylcholinesterase (BChE) is a plasma enzyme known for its role in hydrolyzing ghrelin and bioactive esters, and is associated with altered metabolisms. Serum BChE is reduced in several cancer types. In this thesis we revealed a biphasic alteration of BChE and identified its downregulation at early stage of PC and upregulation at advanced stage PC. In a similar manner, we reported a functional role of CNTN1 in PC advancement. We demonstrate evidence for CNTN1-mediated enhancement of LNCaP cell proliferation in vitro and formation of CRPC in vivo, as well as its oncogenic potency in a prostate-specific CNTN1 transgenic model. Furthermore, we constructed a novel CNTN1-associated gene panel that predicts PC relapse risk with high robustness. IQGAP1 is critical in cytoskeletal dynamics which underlies cancer progression, metastasis, and PCSC biology. We showed IQGAP1 downregulation in both CRPCs and advanced PCs, and constructed a 27-gene signature using differentially expressed genes (DEGs) relative to this downregulation. This IQGAP1-relevant 27-gene panel robustly predicts PC relapse following radical prostatectomy and shows high translational value as a complementary panel to currently available commercial multigene panels. PCSK9 is an important protein in the regulation of cholesterol metabolism but its role in cancer is not known. We provide a comprehensive set of evidence supporting its role in the formation of CRPC, likely via mechanisms involving enhanced intratumoral uptake and sustained AR signalling under androgen-deprived conditions. Importantly, bigenic TRAMP mice deficient in PCSK9 have shown significantly prolonged survival and reduced metastasis.
Collectively, we identified four factors with pivotal roles in PC development and progression into CRPC, albeit with different mechanisms. The altered expression of these factors in advanced PC and their widespread impact on a diverse range of mechanisms important in cell proliferation and survival underscores the importance of PCSCs in promoting advanced prostate cancer. Taken together, the findings of this thesis will advance our knowledge on PCSC-relevant pathways and their association with prostate cancer progression and metastasis. / Thesis / Doctor of Philosophy (Medical Science)
|Contributors||Tang, Damu, Medical Sciences|
|Source Sets||McMaster University|
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