Evolution on experimental animal model for upper urothelium carcinogenesis.
OBJECTIVE
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 (alpha-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 alpha-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.
Reis
Leonardo O
LO
Department of Urology, Division of Urologic Oncology, School of Medicine, University of Campinas, R. Votorantim, 51, ap. 43, Campinas, SP, 13073-090, Brazil. reisleo@unicamp.br
Fávaro
Wagner J
WJ
Ferreira
Ubirajara
U
Billis
Athanase
A
Fazuoli
Mariana G
MG
Cagnon
Valéria H A
VH
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001706:Biopsy; D002951:Citrates / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007679:Kidney Medulla / Q000000981:diagnostic imaging / Q000473:pathology; D008770:Methylnitrosourea / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D000077559:Sodium Citrate; D014513:Ureter / Q000000981:diagnostic imaging / Q000473:pathology; D001743:Urinary Bladder / Q000000981:diagnostic imaging / Q000473:pathology; D014567:Urography; D014571:Urologic Neoplasms / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology*; D019459:Urothelium / Q000000981:diagnostic imaging / Q000473:pathology*
D000477:Alkylating Agents; D002951:Citrates; D000077559:Sodium Citrate; D008770:Methylnitrosourea