Evolution on experimental animal model for upper urothelium carcinogenesis

• Published in: World journal of urology 2010-08, Vol.28 (4), p.499-505
• Main Authors: Reis, Leonardo O., Fávaro, Wagner J., Ferreira, Ubirajara, Billis, Athanase, Fazuoli, Mariana G., Cagnon, Valéria H. A.
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Animals; Biological and medical sciences; Biopsy; Citrates - toxicity; Disease Models, Animal; Female; Kidney Medulla - diagnostic imaging; Kidney Medulla - pathology; Medical sciences; Medicine; Medicine & Public Health; Methylnitrosourea - toxicity; Nephrology; Nephrology. Urinary tract diseases; Oncology; Original Article; Rats; Rats, Inbred F344; Ureter - diagnostic imaging; Ureter - pathology; Urinary Bladder - diagnostic imaging; Urinary Bladder - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Urography; Urologic Neoplasms - chemically induced; Urologic Neoplasms - diagnostic imaging; Urologic Neoplasms - pathology; Urology; Urothelium - diagnostic imaging; Urothelium - pathology
• ISSN: 0724-4983; 1433-8726
• DOI: 10.1007/s00345-010-0545-3

Purpose No optimal, well designed and reproducible animal model for upper urothelial carcinogenesis exists. This study characterized the histopathological features on top of immunolocalization of alpha-dystroglycans (α-DG) and matrix metalloproteinase (MMP-9) and cell turn-over in the upper urinary tract using a novel experimental model. Methods Seventy-five female Fischer 344 rats were divided into three groups: the control group received a 0.30-ml dose of 0.9% physiological saline; the MNU group (chemical carcinogen N -methyl- N -nitrosourea) received 0.30 ml of MNU; and the MNU-citrate group received 0.30 ml of MNU plus sodium citrate, every one intravesically every other week for a total of 4 doses. After 15 weeks, bladder, ureters and renal pelvis were collected for morphological and molecular analysis. Results Associated management with MNU and sodium citrate was able to lead to 100% of both urinary bladder and upper urinary tract tumors, being the high-grade noninvasive papillary urothelial carcinoma the most frequent lesion. The upper urothelium showed reduced α-DG and increased MMP-9 and Ki-67 immunoreactivities in the MNU-citrate group in relation to the other groups. MNU group presented no upper urothelium tumor and 100% bladder tumor. Conclusions This is a relevant evolution on experimental animal model for upper urinary tract carcinogenesis field. MMP-dependent disruption of the DG complex plays an important role in urothelial tumor carcinogenesis and showed the model applicability and significance. MNU-citrate model could contribute to a better understanding of human upper urothelial cancer development as well as to its local treatment strategies in a near future.