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Title: The functional role of ADAMTS-1 and -15 in prostate cancer progression
Author: Molokwu, Chidi
ISNI:       0000 0004 2746 0875
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2011
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Introduction: Prostate cancer is a leading cause of cancer death in men. Death is usually a consequence of castration resistant tumour progression. Some metalloproteinases are implicated in the process of cancer progression. ADAMTS proteinases (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) are metalloproteinases that play diverse roles in tissues. Prostate cancer cells express ADAMTS-1 and -15 but the role played by these proteinases in prostate cancer progression is unknown. This study was designed to determine the role of ADAMTS-1 and 15 in prostate cancer progression. Materials & Methods: Prostate cancer and stromal cell tumour spheroids were grown in 3-dimensional culture in ECM gel containing a quenched-fluorescent substrate. The tumour spheroids were observed for evidence of proteolytic activity. Prostate cancer cells were treated with DHT and TNF. Changes in expression of ADAMTS-1 and -15 were analysed. ADAMTS-1 and -15 expression was knocked-down in PC3 prostate cancer cells and the effect of knock-down on proliferation, migration and invasion was analysed. Results: Tumour spheroids emitted fluorescence after approximately 24 hours in culture, indicating proteolytic activity. DHT and TNF down-regulated ADAMTS-15 expression in LNCaP cells and stromal cells respectively. The validated anti-ADAMTS- 15 antibody detected 50kDa bands, suggesting a novel cleavage site within the disintegrin-like domain of ADAMTS-15. ADAMTS-1 and 15 knock-down had no effect on proliferation, migration or invasion of PC3 prostate cancer cells. Conclusions: Prostate cancer and stromal cells degrade components of the surrounding ECM. ADAMTS-15 but not ADAMTS-1 expression is androgen and TNF-regulated. ADAMTS-1 and 15 expression do not affect the proliferation, migration or invasive potential of PC3 cells in vitro. Cleavage of ADAMTS-15 in the disintegrin-like domain results in the release of a C-terminal fragment with potential anti-angiogenic properties. Down-regulation by DHT in prostate cancer cells suggests that ADAMTS-15 could be playing an anti-tumour role in prostate cancer progression.
Supervisor: Buttle, David ; Hamdy, Fredrick Sponsor: Royal College of Physicians & Surgeons of Glasgow ; BMI Thornbury Hospital ; National Cancer Research Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available