Radiation cystitis modeling: A comparative study of bladder fibrosis radio‐sensitivity in C57BL/6, C3H, and BALB/c mice

• Published in: Physiological reports 2020-02, Vol.8 (4), p.e14377-n/a
• Main Authors: Zwaans, Bernadette M. M., Wegner, Kyle A., Bartolone, Sarah N., Vezina, Chad M., Chancellor, Michael B., Lamb, Laura E.
• Format: Article
• Language: English
• Subjects: Animals; Bladder; Cancer therapies; Cell death; Cellular and Molecular Conditions, Disorders and Treatments; Collagen; Collagen (type I); Collagen (type III); Collagen - genetics; Collagen - metabolism; Cystitis; Cystitis - etiology; Cystitis - genetics; Cystitis - pathology; Diabetes; Disease Models, Animal; Extracellular matrix; Females; Fibrosis; Frequency; Genetic factors; Genotype; Hematuria; Histology; Laboratories; Lamina propria; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mucosa; Original Research; Patients; Physiology; Prostate cancer; Radiation Cystitis; Radiation Injuries, Experimental - etiology; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - pathology; Radiation therapy; Radiation Tolerance; Radiotherapy - adverse effects; Renal Conditions, Disorders and Treatments; Stromal cells; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder - radiation effects; Urogenital system
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14377

A subset of patients receiving radiation therapy for pelvic cancer develop radiation cystitis, a complication characterized by mucosal cell death, inflammation, hematuria, and bladder fibrosis. Radiation cystitis can reduce bladder capacity, cause incontinence, and impair voiding function so severely that patients require surgical intervention. Factors influencing onset and severity of radiation cystitis are not fully known. We tested the hypothesis that genetic background is a contributing factor. We irradiated bladders of female C57BL/6, C3H, and BALB/c mice and evaluated urinary voiding function, bladder shape, histology, collagen composition, and distribution of collagen‐producing cells. We found that the genetic background profoundly affects the severity of radiation‐induced bladder fibrosis and urinary voiding dysfunction. C57BL/6 mice are most susceptible and C3H mice are most resistant. Irradiated C57BL/6 mouse bladders are misshapen and express more abundant collagen I and III proteins than irradiated C3H and BALB/c bladders. We localized Col1a1 and Col3a1 mRNAs to FSP1‐negative stromal cells in the bladder lamina propria and detrusor. The number of collagen I and collagen III‐producing cells can predict the average voided volume of a mouse. Collectively, we show that genetic factors confer sensitivity to radiation cystitis, establish C57BL/6 mice as a sensitive preclinical model, and identify a potential role for FSP1‐negative stromal cells in radiation‐induced bladder fibrosis. Radiation cystitis, a severely debilitating condition characterized by fibrosis, vascular damage, and compromised bladder function, develops in cancer survivors who received pelvic radiation treatment. This is the first study to compare the effects of radiation on the bladder across different murine genetic backgrounds, which may explain differences in patients’ sensitivity to developing radiation cystitis after radiation cancer treatment.