title: Evolution on experimental animal model for upper urothelium carcinogenesis.
abstract: 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.
authors.affiliation: 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
authors.forename: Leonardo O
authors.initials: LO
authors.lastname: Reis
authors.forename: Wagner J
authors.initials: WJ
authors.lastname: Fávaro
authors.forename: Ubirajara
authors.initials: U
authors.lastname: Ferreira
authors.forename: Athanase
authors.initials: A
authors.lastname: Billis
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Fazuoli
authors.forename: Valéria H A
authors.initials: VH
authors.lastname: Cagnon
mesh_terms: 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*
chemical_list: D000477:Alkylating Agents; D002951:Citrates; D000077559:Sodium Citrate; D008770:Methylnitrosourea