Study on the pathophysiological mechanism responsible for lower urinary tract symptoms associated with early prostate cancer using an animal model

Abstract

Lower urinary tract symptoms (LUTS) are a constellation of urination symptoms including urine frequency urgency incontinence and voiding difficulty In the male LUTS are often associated with benign prostatic hyperplasia (BPH) However LUTS are also caused by prostate cancer Reports showed that more than one-third of general practitioners perceived a link between LUTS and early prostate cancer; 66% would carry out prostate speci?c antigen (PSA) screening in men with bothersome LUTS Prostate cancer (PCa) can induce tissue changes and release of neurotransmitters or inflammatory mediators in the microenvironment of the lower urinary tract including the bladder and urethra However the biological mechanism of how a malignant process in the prostate leads to LUTS is still undefined In addition an important clinical question remains whether there is a difference in LUTS presentation between benign and malignant prostate disorders If so can we detect early PCa based on its LUTS characteristics? We postulate that the presence of PCa can induce tissue changes and release of biological mediators in the microenvironment of the urinary bladder thus leading to the development of LUTS This study aimed to elucidate the functional structural and biochemical alteration of the urinary bladder in a mouse model of localized PCa For in vivo experiments we developed an orthotopic model of human PCa An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD-SCID mice Cancer growth was quantified by luciferase-based in vivo imaging system (IVIS) serially every seven days Mice were divided into three experimental groups: 1 mice with sham operation but no injection; 2 mice with injection of sterile saline in the prostate; and 3 mice with injection of DU145 cell suspension in the prostate Comparisons were made for urodynamic parameters bladder histology and biological markers until the sixth week Bladder wall structural changes were assessed by the bladder wall thickness and degree of fibrosis Biomarker expressions in bladder tissue including muscarinic M2 receptor TRPV4 Bax and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy DU145 cell growth in the prostate were successfully monitored by luciferase-based IVIS after orthotopic injection Using our injection technique no anatomical obstruction of the bladder outlet and urethra were noted up to six weeks after injection On the other hand the presence of PCa induced changes in urinary bladder histology biomarkers and urodyanmic parameters Cystometry showed features of detrusor overactivity with increased voiding frequency and high amplitude voiding contractions from the fourth week onward Histological analyses four weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis Immunohistochemistry showed increased expressions of bladder M2 TRPV4 Bax and caspase3 in the PCa mice as early as in the first or second week In conclusion our study has demonstrated that early PCa can induce bladder microenvironment changes involving neural receptors and biological mediators leading to histological and functional alterations even in the absence of overt anatomical obstruction

Date of Award	2020
Original language	English
Supervisor	Yuh-Shyan Tsai (Supervisor)