Bladder cancer (BCa) is the fourth most common cancer in American men, and was estimated to be diagnosed in 70,530 people and cause 14,680 deaths in the USA in 2010. BCa is also the cancer which has the highest cost from diagnosis to death per patient. The cost in BCa is not proportionate to the incidence of BCa, which indicates that the efficacy of follow-up therapies need to be greatly improved. This thesis is focused on investigation of the impacts of androgen receptor (AR) and vitamin D signaling on BCa development and response to therapy, which would lead to the development of novel therapeutic approaches.
Men have an approximately 3-fold higher risk of BCa than women in the USA, which indicates that sex hormones may be involved in BCa development. Previous studies suggested that both androgen and AR are involved in BCa development by using the general AR knockout (ARKO) mouse model. However, since 90% of BCa are derived from urothelium, it would be of interest to determine if urothelial AR plays a role in bladder tumorigenesis.
To address this question, we generated the urothelial ARKO mouse model and applied two BCa mouse models: chemical N-butyl- N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa and UPII-SV40T transgenic mouse BCa models. We found that knocking out urothelial AR decreased bladder tumorigenesis and tumor growth in the BBN-induced BCa mice. Consequently, BBN-treated urothelial ARKO mice had a higher survival rate than wildtype BBN-treated mice. Moreover, the mechanisms by which urothelial AR promotes BCa initiation and growth is via inactivation of p53. Therapeutic targeting of AR by AR degrading enhances ASC-J9 to decrease BBN-induced bladder tumorigenesis. In summary, we provide multiple evidences to support pro-cancer roles of AR in BCa development, and targeting urothelial AR might be therapeutically beneficial. Around 80% of BCa patients are first diagnosed with non-muscle invasive tumors, and often treated with the transurethral resection of bladder tumor (TURBT) surgery to remove the tumors, followed by a series of intravesical therapies to eliminate the residual cancer cells and prevent recurrence. Bacillus Calmette-Guerin (BCG) has been the most effective immunotherapy for nonmuscle invasive BCa for decades. However, the responses to BCG treatment vary among patients and the mechanisms of BCG actions in BCa have not been completely understood, which limits the utility of BCG therapy.
Vitamin D is associated with both innate and adaptive immune responses and has beneficial effects in BCG therapy in tuberculosis (TB) patients, which provides the rationale that vitamin D may contribute to BCG immunotherapy of BCa. To examine the impact of vitamin D signaling on BCG therapy of BCa, we applied both in vitro and in vivo models. We found that the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25-VD), can synergize with BCG to induce BCa cells to secrete higher level of interleukin-8 (IL-8), which results in recruiting more innate immune cells toward BCa cells. Those infiltrating immune cells can suppress BCa cell growth under BCG stimulation. More importantly, the co-treatment of 1,25-VD with BCG significantly improved BCG efficacy of BBN-induced BCa mice in a pre-clinical trial where mice treated with a 1,25-VD+BCG combination survived much longer than with BCG alone. This result suggests that vitamin D signals are critical for BCG therapy responsiveness, and combination therapy might provide a more effective therapy that demands further investigation to optimize the treatment. In summary, we provide ample in vitro and in vivo evidence to elucidate the pro-cancer roles of urothelial AR and vitamin D signals as critical for BCG therapy responsiveness. Targeting these two nuclear receptors’ pathways provides new intervention for preventing BCa development/progression and improving therapeutic efficacy.
|Commitee:||Hilf, Russell, King, Michael, Puzas, Edward, Simpson-Haidaris, Patricia|
|School:||University of Rochester|
|Department:||School of Medicine and Dentistry|
|School Location:||United States -- New York|
|Source:||DAI-B 73/07(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pathology, Immunology, Oncology|
|Keywords:||Androgen receptor, Bladder cancer, Interleukin-8, Sex hormones, Vitamin d signaling|
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