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

Abstract

Objectives: To investigate the pathophysiological mechanism leading to lower urinary tract symptoms in prostate cancer (PCa) by using an animal model. Methods: An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD.CB17-Prkdc scid /NcrCrlBltw (NOD-SCID) mice. Cancer growth was quantified by a luciferase-based in vivo imaging system (IVIS) serially every 7 days. 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 acetylcholine receptor 2 (M 2 ), transient receptor potential cation channel subfamily V member 4 (TRPV4), BCL2-associated X protein (Bax), and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy. Results: DU145 cell growth in the prostate was successfully monitored by a luciferase-based IVIS. after orthotopic injection. Using our injection technique, no anatomical obstruction of the bladder outlet and urethra was noted up to 6 weeks after injection. The presence of PCa induced changes in urinary bladder histology, biomarkers, and urodynamic parameters. Cystometry showed features of detrusor overactivity with increased voiding frequency and high-amplitude voiding contractions from the fourth week onward. Histological analyses 4 weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis. Immunohistochemistry showed increased expressions of bladder M 2 , TRPV4, Bax, and caspase3 in the PCa mice as early as in the first or second week. Abbreviations: Bax, BCL2-associated X protein; ICI, intercontractile interval; IVIS, in vivo imaging system; LUTS, lower urinary tract symptoms; MAPK, mitogen-activated protein kinase; M 2 , muscarinic acetylcholine receptor 2; NICE, National Institute for Health and Care Excellence; NOD-SCID, NOD.CB17-Prkdc scid /NcrCrlBltw; PCa, prostate cancer; TRP, transient receptor potential; TRPA1, transient receptor potential cation channel subfamily A member 1; TRPM8, transient receptor potential cation channel subfamily M member 8; TRPV1, transient receptor potential cation channel subfamily V member 1; TRPV4, transient receptor potential cation channel subfamily V member 4. † Both Lin-Nei Hsu and Yuh-Shyan Tsai contributed equally to this work. ‡ Wen-Pin Su contributed as co-corresponding author.